IMR Press / FBL / Volume 26 / Issue 3 / DOI: 10.2741/4901

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Review
Crosstalk between CML cells with HUVECs and BMSCs through exosomes
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1 Department of Medical Biology, School of Medicine, Sanko University, Gaziantep, Turkey
2 Department of Biological and Biomedical Sciences, Graduate Education Institute, Sanko University, Gaziantep, Turkey
3 Department of Medical Biochemstry School of Medicine, Sanko University, Gaziantep, Turkey
4 Department of Molecular Medicine, Graduate Education Institute, Sanko University, Gaziantep, Turkey
5 Department of Internal Medicine and Hematology, Sanko University Sani Konukoglu Application and Research Hospital, Gaziantep, Turkey
Front. Biosci. (Landmark Ed) 2021 , 26(3), 444–467; https://doi.org/10.2741/4901
Published: 1 October 2020
(This article belongs to the Special Issue Oxidative stress, DNA damage and inflammation in carcinogenesis)
Abstract

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by presence of the BCR-ABL fusion gene which encodes the constitutively active BCR-ABL chimeric protein. Imatinib is first FDA approved first-line BCR-ABL targeting drug for the treatment of newly diagnosed CML cases. Nowadays there are recently developed and more efficient TKIs in the market. Despite the improvements in the CML therapy by using tyrosine kinase inhibitors (TKIs) primary/secondary resistance or progression from chronic to accelerated and blastic phase may be developed in some cases. Underlying mechanisms of TKI resistance and disease progression may results from BCR/ABL dependent or independent alterations. Recently it was revealed that tumor microenvironment is very important for cancer cell growth, survival, proliferation, hemostasis, invasion and metastasis. Exosomes derived from tumor cells contain many important signaling molecules and transfer these molecules in the neighbouring cells. In the bone marrow matrix CML cells, CML leukemic stem cells,cells, bone marrow mesenchymal stromal cells can communicate with each other through exosomes. In this review we focused on biological and clinical importance of CML derived exosomes and we will summarize the recent studies in this field.

Keywords
Chronic myeloid leukemia
CML
Exosomes
mi-RNA
angiogenesis
adhesion
migration
drug resistance
bone marrow mesenchymal stromal cells
BMSCs
CML leukemia stem cells
Review
2. INTRODUCTION

CML is a myeloproliferative disorder, characterized by the expansion of pluripotent bone marrow stem cells. The hallmark of the disease is presence of a small derivative chromosome 22 known as the Philadelphia chromosome resulting from a classical balanced reciprocal translocation t(9;22)(q34;q11.2) in leukemia cells. Approximately in 90-95% of the newly diagnosed CML cases balanced t(9;22)(q34;q11.2) translocation could be detected during cytogenetic analysis from bone marrow sampling (1). Variant Philadelphia translocations resulting from translocation between three or more chromosomes could be observed in the remaining 5-10% of the newly diagnosed chronic phase CML cases (2-3). Three different clinical stages are defined for CML including; the chronic phase (CML-CP), the accelerated phase (CML-AP), and the blast crisis (CML-BC). During the progression of the disease through CML-CP to CML-AP and CML-BC increased genomic instability and gradually increased number of structural and numerical chromosomal abnormalities could be detected in CML cells (4).

Translocation of the proto-oncogenic tyrosine-protein kinase ABL1 gene located on chromosome 9 to the breakpoint cluster region (BCR) gene located on chromosome 22 results in generation of a BCR-ABL1 fusion gene on the Philadelphia chromosome in CML cells. Chimeric BCR-ABL1 fusion protein which encoded by BCR-ABL1 fusion gene have constitutive tyrosine kinase activity. Depending on the breakpoints in the BCR and ABL1 genes there are three types of BCR-ABL fusion transcripts including; Major BCR-ABL1 (p210), minor BCR-ABL1 (p190) and micr BCR-ABL1 (p230). In the majority of CML cases only major BCR-ABL1 transcript has been expressed (5).

3. SIGNALING PATHWAYS ACTIVATED IN CML

In the presence of BCR/ABL1 fusion protein ABL1 oncoprotein have constitutive activity and phosphorylate a broad range of signaling proteins which activates different intracellular signaling pathways. These signaling pathways include; JAK/STAT, RAS/RAF/MAPK, PI3K/Akt/mTOR, Hedgehog (Hh), Wnt/beta-Catenin, TGF-beta/TGFBR, Notch signaling pathways involving in cell survival, proliferation, inhibition of apoptosis, alteration in cell adhesion properties, angiogenesis, extracellular matrices remodeling, stemness of leukemia stem cells (6).

3.1. JAK/STAT pathway

JAK/STAT signaling is one of the important pathway which is activated in CML. When a growth factor or a cytokine binds to its receptor it results in; formation of receptor chain aggregate, accumulation of Janus Kinase (JAK1-3 and Tyk2) into close proximity, transphosphorylation of the JAKs at tyrosine residues, cytokine receptor chain phosphorylation, binding of Signal Transducer and Activator of Transcription-proteins (STAT1-4, STAT5A, STAT5B, and STAT6) to phosphotyrosine residues of the receptor tyrosine kinase, tyrosine phosphorylation of STATs through JAKs followed by dissociation of STATs from the receptor tyrosine kinase complex, STAT dimerization through phosphotyrosine-SH2 interactions followed by translocation to the nucleus where they bind to regulatory regions of target genes containing STAT-binding motifs (Cyclin D1, Bcl-X, Mcl1, MDR1, TERT, etc.) (7-9).

3.2. Ras/Raf/MAPK pathway

Second signaling pathway which is activated through BCR/ABL1 is Ras/Raf/MAPK pathway. Binding of a growth factor to its receptor results in; receptor dimerization, tyrosine transphosphorylation of the receptor chains, binding of Growth Factor Receptor Bound protein 2 (Grb2) to phosphotyrosine residues, interaction between Grb2 and Son of Sevenless (SOS), Ras-GDP recruitment to the cell membrane, formation of active Ras-GTP complex, activation of serine/threonine protein kinase Raf-1, activation of MEK, activation of serine/threonine protein kinase MAPKs. There are three branches of the MAPK cascade including; Extracellular signal Regulated Kinase (ERK), c-Jun N-terminal Kinase (JNK), and p38 MAP kinase. Activated ERK translocate into the nucleus where they phosphorylate the transcription factors (c-MYC, Ets, c-Fos, Elk, c-Jun) as substrates and regulate target genes transcription (10).

3.3. PI3K/Akt/mTOR pathway

Phosphatidylinositol-3-Kinase (PI3K) is another target of the BCR-ABL. Activated PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), phosphatase and tensin homologue (PTEN) downregulates signaling cascades induced by PI3K, PIP3 activates phosphoinositide-dependent kinase 1 (PDK1) and Akt (11). Phospo-Akt block both Tuberous Sclerosis 1 and 2 (TSC1 and TSC2) complexes, GTP bound Ras Homolog Enriched in Brain (Rheb) increase and activates its downstream proteins including Mammalian Target of Rapamycin (mTOR) which are the catalytic subunit of two protein complexes: mTORC1 and mTORC2 (12). These two complexes present different compositions and functions. mTORC1, composed by mTOR, Regulatory Associated Protein of mTOR (RAPTOR), mLST6 and PRAS40 activates S6 Kinase (S6K), S6 ribosomal protein (rpS6) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) controlling cell cycle (progression from G1 to S phase), cell proliferation, survival, and angiogenesis. The mTORC2 is composed by mTOR, Rapamycin-Insensitive Companion of mTOR (RICTOR), mLST6, Protein observed with Rictor1 (Protor), and SAPK Interacting protein 1 (mSIN1), regulate cytoskeleton organisation and cell proliferation (13).

3.4. Hedgehog pathway

One of the major pathways influencing CML leukemia stem cells self-renewal potential is the hedgehog (Hh) signaling pathway. Recent studies show that Hedgehog signaling is upregulated in BCR-ABL+ CML progenitor cells and gradually upregulated through the disease progression. There are three isoforms of Hh produced by stromal cells including; Sonic hedgehog (Shh), Desert hedgehog, (Dhh) and Indian Hedgehog (Ihh) (14). Hh proteins secrete by the Dispatched (Disp) into extracellular media. In the absence of Hh, Patched1 (Ptc) inhibits the activity of the Smoothened (Smo). In the receiver cell Hh binds to its receptor Ptc. Binding of Hh to Ptc results in loss of Ptc activity followed by activation of Smo leading to the activation of the glioma-associated oncogene family (GLI1-3) of transcription factors. GLI transcription factors dissociate from Suppressor of Fused (SUFU) and translocate to the nucleus where they regulate the expression of target genes associated with cell cycle, proliferation and survival (CYCLIND,c-MYC, BCL-2 etc.) (15)

3.5. Wnt/beta-Catenin pathway

Wnt signaling also important in CML cell stemness. In the canonical pathway when Wnt signaling is not activated, beta-Catenin marked for degradation by a multiprotein complex that is composed of Axis Inhibitor (Axin), Adenomatous Polyposis Coli (APC) , Glycogen Synthase Kinase 3 (GSK-3), Creatin Kinase 1 (CK1), protein phosphatase 2A (PP2A) and E3-ubiquitin ligase (beta-TrCP) followed by degredation by proteasomes (16). Binding of the Wnt to the its Frizzled (Fzd) receptor iand to the co-receptor Low-density lipoprotein Receptor-related Protein (LRP5/6) results; phosphorylation of Dishevelled (Dvl), formation of LRP aggregates, phosphorylation of LRP receptors, inhibition of degredation complex, and translocation of beta-Catenin into the nucleus (17) . Nuclear beta-Catenin interacts with members of the Tcf/Lef transcription factors (Tcf1, Tcf3-4 and Lef1) and binds to co-activator proteins; PROP paired like homeobox-1 (Prop1), forkhead box O (FOXO), Krueppel-like factor 4 (Klf4) activating the target gene expression including (c-MYC and CYCLIND1, etc.) (18).

3.6. TGF-beta/TGFB1R pathway

Constitutive BCR/ABL activity upregulate the expression of Transforming Growth Factor, Beta-1 (TGF-beta 1) and quiescent CML stem cells express higher levels of TGF-beta 1 TGF-beta binds to TGF-BRII and TGF-BRI dimers which have serine–threonine kinase activity. TGF-BRII homodimer phosphorylates TGF- beta RI homodimers (19). Activated TGF-beta receptor complex recruits Sma-and Mad-Related Protein 2-3 (Smad2-3) and phosphorylates them. Phosphorylated Smad 2 and 3 form a trimeric complex with Smad4 which translocate to the nucleus and regulate target gene expression. In the route of non-canonical TGF-beta pathway Erk, JNK and p38 MAP kinase and PI3K-Akt pathways are also activated. Activation of PI3K-Akt-NF-kB pathway results in upregulation of Matrix Metalloproteinase 9 (MMP9), which further stimulates the expression of Kit Ligand (sKITL) and Intercellular Adhesion Molecule-1 (sICAM-1) (20). S-ICAM-1 prevents the CML cells from the recognition by T lymphocytes and natural killer cells while s-KITL leads to mobilization of CML cells to the peripheral circulation. TGF-beta-Akt signalling also induce the FoxO3a pathway, leading to CML-initiating cells maintenance (21)

3.7. Notch pathway

Another signaling pathway important in proliferation, cell survival, and hematopoietic stem-cell self-renewal is Notch pathway. Notch receptors (Notch1–4) have been activated through interaction with their ligands including; Serrate-like Jagged1-2 (JAG1–2) and Ligand of the Delta-like (Delta1, 3-4) (22). Notch extracellular domain (NECD) present on the membrane of signal-receiving cells binds Notch ligands expressed on the membrane of signal-sending cells. This receptor-ligand interaction mediates two sequential proteolytic cleavages in the Notch through A-Disintegrin and Metalloprotease-10 and 17 (ADAM-10, ADAM-17) and Presenilin (PS)/γ-secretase complex (23). After these cleavages Notch intracellular domain (NICD) translocate to the nucleus. In the nucleus NICD associates with Recombination Signal-Binding Protein for Immunoglobulin Kappa J Region (RBPJ) and Mastermind-like1-3 (MAML1-3) resulting in activation of target genes transcription including; Hairy/Enhancer of Split 1/5 (HES1/5), Hairy/Enhancer of Split-Related with YRPW Motif (HEY), Myc, cyclinD, Pre-T-Cell Receptor, Alpha-Chain Precursor (pTalpha), and JAG1 (24).

4. TYROSIN KINASE INHIBITORS (TKI) IN CML

Detection of importance of BCR/ABL oncoprotein in CML led to improvements in researches on drug design and development targeting this oncogenic protein. Imatinib mesylate was the first TKI to receive the Food and Drug Administration (FDA) approval for the treatment of patients with CML-CP. Imatinib binds to the BCR-ABL1 tyrosine kinase domain, change the conformation of ATP binding site and prevent the phosphorilation of the substrate proteins (25). In newly diagnosed CML cases having first-line imatinib mesylate therapy approximately 20% of the cases discontinues the therapy due to intolerance to the drug and approximately another 20% of the cases develops drug resistance during the therapy. First imatinib resistance mechanism was acquired point mutations in the kinase domain of BCR/ABL gene during the disease progresssion. (26). This observations led to the development of second and third generation tyrosine kinase inhibitors that targeting a large spectrum of tyrosine kinase proteins in addition to BCR-ABL including; Nilotinib, Dasatinib, Bosutinib, (Second Generation TKI), Radotinib, and Ponatinib (Third Generation TKI) (27).

Among the second generation TKIs, Nilotinib inhibits the kinase activity of BCR-ABL mutant cell lines except those carrying the T315I mutation and also inhibits Platelet-Derived Growth Factor Receptor (PDGFR-alpha and PDGFR-beta) and c-Kit (28). Dasatinib is a more potent inhitibor of BCR/ABL compared with Imatinib and Nilotinib which inhibit the kinase activity of wild-type and BCR-ABL mutant cell lines except those carrying the T315I mutation. Dasatinib also inhibits Src family of kinases (Fyn, Yes, Src, and Lyk), Ephrin Receptor A2 (EphA2), PDGFR, and c-Kit in addition to BCR-ABL (29). Third second-line TKI for CML is Bosutinib. Bosutinib is a dual Src and ABL TKI which inhibits kinase activity of wild-type and BCR-ABL mutant cell lines except those carrying T315I and V299L mutations (30).

Among the third generation TKIs, Radotinib inhibits wild-type and mutant BCR-ABL1 with the exception of T315I. In addition to BCR/ABL Radotinib targets c-Kit, PDGFR and SRC. This drug is currently approved in only South Korea for treatment of newly diagnosed CML cases and insensitive to other BCR/ABL TKIs (31). Another third generation TKI, Ponatinib inhibits wild-type and BCR-ABL mutant cell lines including those carrying the T315I mutation. Ponatinib also inhibits Vascular Endothelial Growth Factor Receptor (VEGFR), PDGFR, Epidermal Growth Factor receptor (EGFR), SRC, KIT, Rearranged During Transfection (RET), FMS-Related Tyrosine Kinase 3 (FLT3) in addition to BCR-ABL (32).

Despite of the improvements in drug development and treatment strategies, in some of the cases resistance to TKIs developed through ABL independent mechanisms including; activation of alternative pathways, gain of non-random chromosomal abnormalities, mutations in the genes associated with DNA repair mechanism, increased activity of multidrug-resistance proteins, variations in cytochrome P450 enzymes, quiescent CML stem cells, epigenetic and microenvironmental alterations regulated by mesenchymal stromal cells, the immune cell contexture in the bone marrow microenvironment (33-34).

Recently it has been demonstrated that exosomes released from CML cells play important roles in cell-cell communication, drug resistance, quiescent CML cell stemness, modulation of cell adhesion, extracellular niche reorganisation, neovascularization and drug resistance. According to recent reports cell to cell communication among CML cells and Endothelial Cells (EC) and Bone Marrow Mesenchymal Stromal Cells (BMSCs) may be involved in drug unresponsiveness or resistance to the drugs, cell surveillance and stemness of CML cells.

5. EXOSOMES

Exosomes are microvesicles (30–150 nm) produced by endocytic network and released from all cell types under physiological as well as pathological conditions into extracellular space. Inward budding of endosomal membranes results in the accumulation of intraluminal vesicles (ILVs) within the large multivesicular bodies (35). Endosomal Sorting Complexes Required for Transport (ESCRT) complexes play important roles in the formation of MVBs. During this process, some cytosolic components including; proteins, lipids and RNAs are sorted into ILVs (36). In addition to ESCRT dependent pathway, exosome biogenesis is also regulated through an ESCRT independent pathway. In this pathway conversion of sphingomyelin to ceramide by Sphingomyelinase (nSMase) play an important role in the ILVs formation. (37). After the fusion of MVB membranes and plasma membranes, content of the ILVs secreted from cells as exosomes. They could be isolated from many body fluids including plasma, urine, semen, saliva, bronchial fluid, cerebral spinal fluid, breast milk, serum, amniotic fluid, synovial fluid, tears, lymph, bile, and gastric acid. There are several exosome isolation methods based on ultracentrifugation, precipitation, targeted filtration, affinity using magnetic beads, size exclusion chromatography which have advantages or disadvantages over each other (38).

Due to exosome formation and release require ESCRT pathway, proteins of this pathway and its accessory proteins including Alix, Tumor Susceptibility Gene 101 (TSG101), Heat-Shock Cognate Protein 70 (HSC70), and Heat Shock Protein 90 (HSP90) have been found in exosomes regardless of the secreting cell type. In some cells, release of exosomes into the extracellular space depends on sphingomyelinase enzyme activity. In the exosomes released through this pathway tetraspanin family transmembrane proteins including CD9, CD63 and CD81 are enriched in exosomes. Therefore, this set of proteins are called as “exosomal marker proteins.” And different combinations of these proteins have been used in exosome characterization (39).

Physical characterization of the exosomes could be done by using different techniques including; Nanoparticle Tracking Analysis (NTA), Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM) and Tunable Resistive Pulse Sensing (tRPS). NTA, DLS and TRPS techniques allows to estimate the particle size and concentration. In addition, exosome concentration could be estimated by using colorimetric quantitation of Acetylcholinesterase activity in the exosomes. TEM and SEM have been used for evaluation of exosomal vesicles morphology (40).

Exosomes contain variety of molecules such as receptors, transcription factors, enzymes, extracellular matrix proteins, microRNAs, long-noncoding RNAs, mRNAs, DNA fragments, lipids and some other metabolites, and their content is affected by different environmental factors and health status. After the secretion of exosomes from secreting cells they can fuse with recipient cells and affect the intrasellular signaling pathways and metabolism (41).

Recently, it has been documented that; exosomes play important roles in intercellular signal transduction, cell proliferation, cancer progression, regulation of tumor microenvironment, drug resistance, invasion, metastasis, immunosuppression, angiogenesis in various types of the cancer especially in solid tumors (42-43). There are, published reports on importance of exosomes in CML cell viability, survival and stemness based on cell-cell communication among CML cells, endothelial cells and BMSCs. In this review, we focused on biological and clinical importance of CML cell derived exosomes and exosomal factors.

6. EXOSOMAL CROSSTALK AMONG CML, ENDOTHELIAL and BMSCs
6.1. Selective miRNA expression in CML derived exosomes

Feng et al., (2013) compared miRNA profile of the parental K562 cells and the exosomes of them by microarray analysis. They observed that miRNA expression profile of K562 cells and their exosomes were vary similar. Interestingly, 49 miRNAs expression levels were found to be up-regulated in exosomes compared to K562 cell extracts. Bioinformatical analysis demonstrated that among these 49 up-regulated miRNAs, 25 is associated with the cell cycle, antiapoptosis, cell adhesion, Wnt signaling, angiogenesis, tumor invasion and metastasis, mesenchymal cell proliferation, and cell migration. Among the miRNAs upregulated in exosomes, twenty one were modulators of the Wnt signaling pathway. They also reported that, adherens junction and focal adhesion pathways were also important which were modulated by 19 different miRNAs enriched in K562 derived exosomes (44). Their results suggest that miRNA profiles of parental CML cells and exosomes derived from them might be different. This diversity might be regulated by intracellular mechanisms and provides the advantage to CML cells survival and proliferation.

6.2. Effects of exosomes on autocrine cell growth in CML

It’s reported by Raimondo et al., 2015, expression of TGF-beta 1 is higher in exosomes compared with LAMA84 cells that they have TGF-beta 1 receptors at their plasma membrane. Treatment of LAMA84 cells with LAMA84 derived exosomes results in; an increase in the colony formation and proliferation rate, elevation of phospho-SMAD 2/3, elevation of phospho-Akt, phospho-ERK and total Nuclear Factor-kappa B (NF-kB) protein levels. Treatment of LAMA84 cells with LAMA84-derived exosomes leads to reduction of the pro-apoptotic BCL2-Associated Agonist of Cell Death (BAD), BCL2-Associated X (BAX), p53-Upregulated Modulator of Apoptosis (PUMA) proteins expressions and an elevation in the anti-apoptotic BCL2-Related Protein, Long Isoform (BCL-xl), BCL2-Like 2 (BCL2L2) and survivin proteins expressions. Co-treatment of LAMA84 cells with exosomes and TGF-beta 1 receptor inhibitor (SB) or anti-TGF-beta 1 antibody reverses all of these fidings. It is also observed in Non Obese Diabetic/ Severe Combine Immunodeficient (NOD/SCID) mice model after 50 days exosome-treated mice develops larger tumors compared with exosome untreated mice. Phospho-ERK, phospho-Akt and total NF-kB protein levels in tumor biopsies obtained from mice treated with exosomes found to be elevated (45). Their results show that, LAMA84 derived exosomes leads to cell survival and proliferation in an autocrine fashion through TGFB1/TGFB1R and activation of both canonical and non-canonical (ERK, PI3K/Akt and NF-kB) pathways in vitro and in vivo models. Also, LAMA84 derived exosomes can activate antiapoptotic molecules while repress pro-apoptotic molecules.

6.3. Crosstalk between CML and endothelial cells through exosomes
6.3.1. Exosomal IL8 mediated crosstalk

Treatment of HUVECs with 50 µg/ml of LAMA84R-derived exosomes or 10 ng/ml recombinant IL8 increase in phospho-Erk½, phospho-Akt, Vascular Cell Adhesion Molecule 1 (VCAM1), ICAM1 and IL8 expression in HUVECs leading to increased adhesion of LAMA84R cells to Human Umbilical Vein Endothelial Cells (HUVECs), tube formation and the length of cellular projections. Incubation of exosome induced HUVECs with IL8 siRNA, neutralizing IL8 antibody or Carboxyamidotriazole orotate (CTO) reverses of the affects of exosomes on HUVECs (46).

Protein profiling analysis revealed that contents of LAMA84 cell lines and of exosomes are different. Incubation of HUVECs with LAMA84-derived exosomes, exosomes isolated from CML patients or recombinant IL8 leads to dose- and time-dependent increase in phospho-MAPK p42/44 level, VCAM-1, ICAM-1 and IL8 expressions in HUVECs and LAMA84 cell, and also increase in adhesion to HUVEC monolayer, endothelial cell migration, formation of tubular connections. Incubation of HUVECs with LAMA84-exosomes results in decreased cadherin expression with granular cytoplasmic localization and translocation of beta–catenin from the plasma membrane to the nucleus. However, incubation of HUVECs with IL8 neutralizing antibody reverses all effects of IL8 (47).

Incubation of HUVECs with K562 exosomes, exosome lysates or recombinant IL8 increase tube formation and angiogenesis in a dose-dependent manner. PKH26-labeled exosomes have been internalized by HUVECs and accumulated in the perinuclear region of the cell during early tubular organization. In the cells reorganizing and sprouting extensions, exosomes move towards the cell periphery and into pseudopods. Within tubular network, exosomes might translocate from cell to cell. In HUVECs treated with K562 exosomes 416Y-Src level and Phospho-Src localization level at membrane interaction regions have been found to be increased (48).

6.3.2. Exosomal miR-210 mediated crosstalk

Incubation of K562 cells under hypoxic conditions for 48–72 h results in elevated expression of Hypoxia Inducible Factor 1 Alpha (HIF-1 alpha). Under hypoxic conditions miR-18b and miR-210 have been overexpressed in both K562 cells and their exosomes. K5621%O2-exosomes containing miR-210 increase the tube and capillary-like structure formation from HUVECs. Exosomal miR-210 directly binds 3’ UTR region of the Ephrin A3 (EFNA3) mRNA (anti-angiogenic factor) and degrade it in HUVECs. Treatment of HUVECs with K5621%O2-exosomes under normoxic conditions suppress EFNA3 expression. Transduction of K562 cells with miR-210 inhibitor cultured under hypoxic conditions led to a decrease in endothelial tube formation by HUVECs (49).

Tissue Inhibitor of Metalloproteinase 1 (TIMP-1) overexpression results in upregulation of miR-210 in lung adenocarcinoma cell line A549 through CD63/PI3K/Akt/HIF-1 pathway, accumulation of miR-210 in exosomes, and increased tube formation and angiogenesis in HUVECs, promoted by miR-210 including exosomes (50). It is also reported that, under the hypoxic conditions HIF-1 alpha up-regulate the miR-210 expression in response to the low oxygene condition in tumor cells and in their exosomes breast cancer cell lines MCF7, MDA-MB 231 and SKBR3 and human lung adenocarcinoma cell line A549 (51-52). Exosomes isolated from the sera of Hepatocellular Carcinoma (HCC) patients and from QGY-7703, HepG2, SK-Hep-1, and Huh-7 cell lines have increased miR-210 level and transfection of HUVECs with miR-210 induce HUVECs to form capillary-like structures and tubulogenesis (53). nSMase2 expression, exosome secretion and miR-210 expression in exosomes is higher in breast cancer cells lines (4T1 cells, MDA-MB-231-D3H1 and MDA-MB-231-D3H2LN) than in normal mammary epithelial cell line (MCF10A). Exosomes and miR-210 transferred from breast cancer cell lines to HUVECs increase the tube formation of HUVECs and metastatic potential of the cancer cells while decrease EFNA3 expression.nSMase2 knocked down and nSMase2 inhibitor (GW4869) reduce transfer of miRNA-210 including exosomes from 4T1- and MDA-MB-231 cells to endothelial cells lung metastatic potential with lower endothelial cell density (54). miR-210-mediated down-regulation of EFNA3 in HUVECs results in increased expression of VEGFR2 which promotes increased VEGF expression and leads to angiogenesis and tubular structure formation from endothelial cells (55). In HCC patients, high miR-210 expression was significantly correlated with poor prognosis and positively correlated with microvascular density (56). miR-210 overexpression also inhibits the expression of sprouty-related protein-1 (SPRED1) and Phosphatidylinositol-3-Kinase Regulatory Subunit 2 PIK3R2 in HUVECs (57).

According to literature we propose cell to cell communication between leukemia cells and HUVECs through miR-210 including: hypoxia induced HIF-1 alpha expression through CD63/PI3K/Akt/HIF-1 pathway, upregulated nSMase2 expression, HIF-1 alpha induced miRNA-210 upregulation and exosomal secretion, internalization of exosomes from HUVECs, increase in phospho-Erk, -Akt, -Src and -Focal Adhesion Kinase (FAK), downregulation of cytoplasm EFNA3, SPRED1 and PIK3R2, increased expression of VEGFR, VEGF, ICAM and VCAM, mislocalisation of e-Cadherin into cytoplasm translocation of Catenin into the nucleus, expression of IL8. This signaling cascade results in increased vascularisation and angiogenesis in the extracellular niche.

6.3.3. Exosomal miR-17-92 cluster mediated crosstalk

The members of miR-17-92 gene cluster (miR-17, miR-18a, miR-19a, miR-20a, miR-19b, miR-92a) are overexpressed in K562 cell line. miR-92a packaged in K562 exosomes have been transferred from K562 cells to HUVECs in vitro co-culture system. However, incubation of miR-92a overexpressing K562 cells with nSMase inhibitor (GW4869), miR-92a expression level decrease in HUVECs. miR-92a binds 3′-untranslated region of the Integrin α5 (ITGA5) mRNA and decrease the expression of it. Treatment of HUVECs with K562 exosomes overexpressing miR-92a increase the number of migrated HUVECs Also, HUVECs cultured on matrigel treated with K562 exosomes overexpressing miR-92a predispose to form the tube-like structures (58).

miR-17-92 cluster genes upregulated in multiple tumor types (lung, breast, stomach, prostate, colon and pancreatic cancer) but their role in angiogenesis is still controversial. Overexpression of miR-92a in blood samples of colorectal cancer patients associated with invasiveness. And also, expression level of miR-92a were increased in colon cancer cell lines DLD-1, COLO201, SW480, and WiDr. Dickkopf 3 (Dkk-3) is a potential target of miR-92a in colon cancer and Dkk-3 is downregulated in colon cancer cell lines, miR-92a including MVs transferred into the HUVECs through exosomes increase motility and tube formation ability of HUVECs (59). miR-92a-3p levels in the exosomes were higher than those within in colon cancer cell lines DLD-1, COLO201, SW480, and WiDr. Claudin 11 (CLDN11) which encodes integral components of tight junctions another target of miR-92a-3p. miR-92a-3p mediated downregulation of CLDN11 promote proliferation, migration, and tube formation in HUVECs. These results indicate that CLDN11 downregulation by exosomes containing miR-92a-3p increase the angiogenesis in endothelial cells (60). Treatment of HUVECs with VEGF, increase the expression of miR-17–92 cluster genes through VEGF/ERK/ELK-1 pathway, proliferation and angiogenic sprouting of endothelial cells, decrease expression of PTEN and Thrombospondin 1 (THBS1-antiangiogenetic factor) in HUVECs (61). Under the prolonged and cyclic hypoxia conditions HUVECs display a distinctive changes in the miRNA expression profile, among those miRNAs miR-19a-5p expression level was decreased during cyclic hypoxia. HIF-1 alpha, Cyclooxygenase-2 (COX-2), Vascular Endothelial Growth Factor (VEGF), VEGFR1, Endothelin 1 (EDN1), and Endothelin-B Receptor (EDNRB) are potential targets of this miRNA, decreased expression of miR-19a-5p results in elevated EDNRB and increased tube formation by HUVECs (62).

These finding show that, effect of the members of miR-17-92 gene cluster on different cellular processes might be different depending on the cell type, physiological conditions and the external factors that the cells expose and miR-17-92 cluster genes induce angiogenesis through upregulation of HIF-1 alpha, COX-2, VEGF, VEGFR1, EDN1, EDNRB, and downregulation of PTEN and CLDN11.

6.3.4. Exosomal miR-126 mediated crosstalk

It is reported that, miRNA-126 level is higher in LAMA84 exosomes than in the parental LAMA84 cells. Incubation of HUVECs with 20–50 μg/ml LAMA84 exosomes resulted up-regulation in miR-126 expression in HUVECs in a dose-dependent manner. miR-126 binds to 3’UTR region of Chemokine, CXC Motif, Ligand 12 (CXCL12; SDF1) and VCAM1 mRNAs and reduce the expression of these proteins in HUVECs. Incubation of HUVECs with 10–50 μg/ml exosomes or miR-126 mimics resulted in decreased LAMA84 cells migration towards HUVEC conditioned medium and ability to adhesion to endothelial monolayer, in a dose dependent manner. Transendothelial migration assay showed that transendothelial migration of LAMA84 cells increased when HUVECs were treated with exosomes for 24 hours (63). According to their results Taverna et al., 2014, speculated that; in the early phases of exosome treatment of HUVECs, VCAM1 expression levels and LAMA84 –HUVEC adhesion is elevated while the late phases of the exposure VCAM1 expression and adhesion capacity is decreased which allows LAMA84 cells migration towards chemoreacttant rich environment.

miRNA-126 targets pro-angiogenic proteins including Insulin-like Growth Factor Binding Protein 2 (IGFBP2),phosphatidylinositol transfer protein Phosphatidylinositol Transfer Protein Cytoplasmic 1 (PITPNC1) and c-Mer Tyrosine Kinase (MERTK) in metastatic breast cancer cell line CN34 LM1a. miRNA-126 frequently downregulated gene in most of the cancers. In this situation MERTK, IGFBP2 and PITPNC1 rescue from inhibition of miRNA-126. IGFBP2 secreted from metastatic cells induces endothalial cell chemotaxis and migration through IGF1/IGF1-R axis. MERTK receptors secreted from metastatic cells also contribute endothelial recruitment through blocking the binding of Growth Arrest-Specific 6 (GAS6) to endothelial MERTK receptors (64). miR-126 expression level is reduced in gastric carcinoma tissues obtained from patients. miR-126 binds to 3′UTR region of VEGF-A and regulate protein expression level of it. Ectopic overexpression of miR-126 in metastatic human gastric cancer cell line SGC-7901 results in reduced microvessel density and reduced VEGF-A expression (65). miR-126 expression level is lower in HSC3 oral cancer cell line which have high metastatic potential than in HSC4 cells compared with a low metastatic potential. Ectopic overexpression of miRNA-126 in HSC3 results in decreased expression of VEGF-A while inhibition of miRNA-126 in HSC4 results in elevated expression of VEGF-A. There is an inverse correlation was between the miR-126 expression levels and microvascular density, angiogenesis in HCC (66). miR-126-3p expression is down-regulated in HCC tumor tissues and a set of HCC cell lines. Microvascular density level is inversely correlated with miR-126-3p expression. Ectopic overexpression of miR-126-3p in HepG2 and SMMC-7721 cells reduce LRP6, PIK3R2 and Phospho-Akt expression levels and reduce micro-vessels and capillary-like structure formation ability of HUVECs. Suppression of miR-126-3p in BEL-7402 increased the angiogenesis ability of HUVECs (67).

According to the literature we can speculate that miRNA-126 is frequently downregulated in most of the tumor types which is inversely correlated with angiogenesis. Downregulation of miR-126 in cancer cells results in increased expression of LRP6 and PIK3R2 in tumor cells which further activates Wnt/beta-Catenin and PI3K/Akt/mTOR signaling pathways. Activation of these pathways induce VEGF expression. Downregulation of miR126 also results in upregulation of other pro-angiogenic proteins including; IGFBP2, PITPNC1 and MERTK expression and secretion from metastatic cancer cells. This may results in activation of VEGF/VEGFR, IGFBP2/IGF1/IGF1R and c-MERTK/GAS6/MERTK cascades in endothelial cells and induces neovascularization. Selective packaging and enrichment of miRNA-126 into exosomes results in increased levels of miRNA-126 in the endothelial cells. miRNA-126 also contribute to migration and adhesion capability and angiogenesis through CXCL12/CXCR4 and VCAM1 modulation in a time dependent fashion.

6.3.5. Exosomal miR-21 mediated crosstalk

Treatment of HUVECs with K562 and LAMA84 exosomes incubated with Curcumin results in; decreased IL8 and MARCKS-Like Protein 1 (MARCKSL1) and VCAM1 expression in HUVECs, plasma membrane localisation of tight Junction marker Zona Occludens 1 (ZO1) and Vascular Endothelial Cadherin (VE-Cadherin) decrease, in endothelial capillary-like structure formation and motility. High levels of miR-21 in exosomes and HUVECs treated by them leads to inactivation of Ras Homolog Gene Family Member B (RhoB) and MARCKSL1 in HUVECs. Taverna et al., 2015, showed that; miR-21 expression level is low in K562 and LAMA84 cells treated with Curcumin while miR-196b is high in these cells. On the contrary, in the exosomes secreted from these cells, miR-21 level is high as miR-126b is low. In Curcumin treated cells miR-21 downregulation results in decreased phospho-Akt and VEGF levels and an increase in PTEN expression in a dose-dependent manner. Increased miR-196b downregulates BCR/ABL mRNA in Curcumin treated CML cells. These molecular alterations correlated with reduced migration of K562 and LAMA84 cells towards in the medium (68-69).

In accordance with the results of Taverna et al. 2015, Liu LZ et al., 2011 indicated that; ectopic overexpression of miR-21 in prostate cancer cell line DU145 results in decreased PTEN expression, increased expression of HIF-1 alpha and VEGF, elevation in microvessel formation and angiogenesis. DU145 cells transfected miR-21 inhibitor increases PTEN expression while decrease phospho-Akt, phospho-ERK, HIF-1 alpha and VEGF expression levels, decrease angiogenesis (70). In breast cancer, miR-21 inhibition impairs angiogenesis by targeting HIF-1 alpha/VEGF/VEGFR2 signaling pathway (71). In these two studies mentioned above exosomal miR-21 content is not analysed. miR-21-5p is overexpressed in exosomes of thyroid carcinoma cell lines BCPAP and KTC-1 incubated under hypoxic contitions and in exosomes from sera of papillary thyroid cancer patients. Exosome mediated transportation of miR-21-5p suppress TGFBI and Collagen Type IV, Alpha-1 (COL4A1) expression while increase endothelial tube formation and angiogenesis in HUVECs (72).

Liu et al., (2017) showed that; miR-21-5p is up-regulated in exosomes isolated serum of the NSCLC patients and associated with poor overall survival in patients (73). Exosomal miR-21 expression in the cerebrospinal fluids is also found to be elevated in glioma patients than that of the control cases (74). miR-196b-5p is overexpressed in exosomes isolated from sera of esophageal adenocarcinoma patients compared with tumor tissue and non-tumor samples (75).

These reports suggest that, upregulation of miR-21 level results in downregulation of PTEN, activation of PI3K/Akt/mTOR and Ras/Raf/MAPK pathways, increased production of HIF-1 alpha and VEGF in tumor cells. Exosomal miR-21 sorting and transportation may be differ between normoxic and hypoxic conditions. Activation of VEGF/VEGFR2 signalling in HUVECs induce angiogenesis, increased secretion from HUVECs. Activation of Rho/Rac/MARCKS axis in HUVECs under normoxic conditions and regulation of TGF-beta signalling under hypoxic condition also may contribute to angiogenesis.

After the unraveling the cell-cell communication of the CML cells and endothelial cells through a recent report showed that newly synthesized antiangiogenic peptide conjugated Gold Nanoparticles can interfere with VEGF/VEGFR axis and can be reduce neoangiogenesis (76).

6.4. Crosstalk between CML cells and BMSCs through exosomes
6.4.1. IL8-CXCR1/CXCR2 mediated crosstalk

Incubation of bone marrow-derived stromal cell line HS5 with 50 μg/ml of LAMA84 exosomes increase secretion of IL8 from HS5 into bone marrow microenvironment. Treatment of LAMA84 cells with 5 or 10 ng/ml of rIL8 for 48 h results in; increased expression and cell surface presentation of Chemokine, CXC Motif, Receptor 1-2 (CXCR1-CXCR2), increase in phospho-Akt levels increased adhesion ability to HS5 in a dose dependent manner and greater colony formation ability in methylcellulose. IL8 treatment also results in greater tumor formation in NOD/SCID mice in xenograft CML tumor model (77). These results show that; HS5 cells secrete IL8 after the treatment with LAMA84 exosomes or rIL8, IL8 binds CXCR1/CXCR2 receptors located on LAMA84 cell membrane, IL8 released from HS5 is able to modulate LAMA84 cells adhesion and motility properties, IL8 in promotes the survival of LAMA84 cells throught PI3K/Akt/mTOR signaling in both in vivo and in vitro models.

6.4.2. Exosomal AREG mediated crosstalk

Ligands of Epidermal Growth Factor https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/epidermal-growth-factorReceptors (EGFRs) include; Epidermal Growth Factor (EGF), Heparin-Binding EGF-Like Growth Factor (HBEGF), Transforming Growth Factor Alpha (TGF-alpha), Betacellulin (BTC), Amphiregulin (AREG), Epiregulin (EREG), Epithelial Mitogen (EPGN) and the Neuregulins (NRG 1–4). The EGFR family includes: EGFR (ErbB1, Her1), ErbB2 (Her2), ErbB3 (Her3) and ErbB4 (Her4). EGFR family signaling induces activation of RAS/MAPK, PLCγ/PKC, PI3K/Akt and JAK/STAT signaling pathways. Stimulation of BMSCs with EGFR ligands increases the production of growth and differentiation factors and cytokines including; VEGF, angiopoietin-2 (ANGPT2), Platellet-Derived Growth Factor BB (PDGF-BB), Granulocyte-Colony Stimulating Factor (G-CSF), Hepatocyte Growth Factor (HGF), and IL6, IL8 in BMSCs (78).

New diagnosed CML patients leukemia cells express EGFR ligands including; HBEGF, EREG and AREG. ​LAMA84 cells and especially their exosomes overexpress AREG protein with respect to parental LAMA84 cells. Incubation of HS5 cells with LAMA84 derived exosomes results in; increased EGFR expression, activated EGFR signaling, increase in expression of Snail Family Transcriptional Repressor 1 (SNAIL) which is a downstream target of EGFR, increased levels of IL8​ and MMP9 (SNAIL target genes), increased Annexin A2 (ANXA2) expression, increased adhesion of LAMA84 cells to stromal monolayer ​(79). AREG is overexpressed in multiple myeloma (MM) cells in a subset of patients and enriched in exosomes compared to parental MM cells (80). MM cell derived exosomes block osteogenic differentiation and increase the release of the pro-osteoclastogenic cytokines (IL6) from BMSCs through the activation of EGFR pathway. Treatment of BMSCs with MM cell derived exosomes increase the adhesion of MM1.S cells to the mesenchymal monolayer (81).

Based on the literature we can speculate that; CML cells and their exosomes express elevated levels of AREG. AREG containing exosomes induces EGFR expression and activation, EGFR signaling pathways induce SNAIL expression which is further induce IL8 and MMP9 synthesis and secretion from BMSCs, increased ANXA2 expression which induce active MMP formation, increased invasion and adhesion capacity, increased IL6 secretion leading to increased osteoclastogenic activity and blockage of osteoblastogenic differentiation.

6.4.3. Exosome mediated crosstalk through undefined mechanism

Incubation of human BMSCs with K562 exosomes influence the expression of various genes associated with osteoclast activation or osteoblast repression including; CXCL12, DKK1, Wnt5a, IL6, Tumor Necrosis Factor Alpha (TNF-alpha) and TGF-beta depending on the exosome concentration and exposure time. Incubation of BMSCs with 50 µg/ml of K562 exosomes increase Nitric Oxide (NO) secretion from BMSCs. Incubation (48 and 72 hr) of BMSCs with K562-derived exosomes decrease the intracellular Reactive Oxygen Species (ROS) level in a dose-dependent manner (82). This increased osteoclastogenic acitivity leads to generation of extracellular milieu suitable for survival of CML cells. There is a significant increase in transcript levels of ROS scavenging enzymes Manganese Superoxide Dismutase (MnSOD) and Catalase (CAT) and reduced ROS levels in CML patients BMSCs co-cultured with K562 CML cells. When BMSCs co-cultured with the K562 cells, they secreted significantly high levels of IL6 and TNF-alpha. This increase in IL6 was mediated by an increased phosphorylation of NFkB in BMSCs during its interaction with the CML cells (83). These findings are correlated with the findings of Jafarzadeh et al., 2019.

6.4.4. Exosomal miR-711 mediated crosstalk

Incubation of BMSCs with K562 exosomes results in exosome mediated transportation of miR-711 into BMSCs. miR722 have a binding site of 3’UTR region of CD44 mRNA. Transfection of BMSCs with miR-711 mimics lead also an increase in miR-711 levels which further decrease CD44 expression in BMSCs (84). Co-culturation of K562 cells and BMSCs with a direct contact between these two cell types results in downregulation of cell surface aminopeptidase-N (CD13), P Glycoprotein 1 (CD44), THY1 (CD90) and Fas (CD95) expression levels in BMSCs. Among these markers CD44 and CD90 are classical mesenchymal stromal cell surface biomarkers (83). Among these especially CD90 is reported to frequently downregulated in BMSCs isolated from leukemia cases. However exact role of this downregulation in leukemogenesis is unresolved (85-86).

6.4.5. Exosomal miR-320 mediated crosstalk

Incubation of human BMSCs with K562 and LAMA84 derived exosomes results in decreased Alkaline Phosphatase (ALP) and in decreased expression of osteogenic markers including; Runt-Related Transcription Factor 2; (RUNX2), Osteopontin (OPN) and Collagen Type I, Alpha-1 (COL1A1), CXCL12 and KITL in a dose-dependent manner. Several miRNAs are overexpressed in K562 and LAMA84 exosomes including; miR-320a/b/c/d, miR-3180-3p, miR-128-3p and miR-423-5p. RNA-binding Protein Heterogeneous Nuclear Ribonucleoprotein A1 (HNRNPA1) have been co-precipitate with miRNA-320a in cytoplasmic lysates of K562 cells and ectopic overexpression of HNRNPA1 results an increase in exosomal miR-320 level but a decrease in intracellular compartments 3'-UTR regions of BCR/ABL and beta-Catenin mRNAs have a binding site for miR-320. HNRNPA1 mediated selective packaging of miR-320a into exosomes results in resque of BCR/ABL mRNA from degradation in CML cells. In BMSCs degradation of beta-Catenin mRNA through miR-320a suppress maturation of osteoblasts (87). miR-320 is a tumor suppressor gene which leads to degradation of BCR/ABL mRNA in CML cells and downregulated in Imatinib resistant CML cases compared with imatinib sensitive patients (88). Recent studies have been shown that miR-320 is down-regulated in various types of cancers, including colon cancer, breast cancer, and acute myelogenous leukemia. miR-320 act as a tumor suppressor gene which repress tumor angiogenesis by targeting Neuropilin-1 (NRP1) in Oral Squamous Cell Carcinoma (OSCC) and frequently downregulated in OSCC (89). MiR-320 have a binding site at the 3′-UTR of Myeloid Cell Leukemia Sequence 1 (Mcl-1) mRNA which is a antiapoptotic activity. Downregulation of the miRNA-320 in human cervical cancer tissues results in upregulation of antiapoptotic protein Mcl-1 (90). miR-320a downregulate the expression levels of beta-Catenin, c-Myc, Cyclin D1 and DKK-1 in the human liver cancer cell line HepG2 cells. However, downregulation of miR-320 expression by using a anti-miR-320a siRNA results in upregulation of beta-Catenin, c-Myc, Cyclin D1 and DKK-1 expression (91). This results indicate that miR-320 is also a tumor suppressor for HCC. HNRNPA1 is an antiapoptotic protein which was reported to be upregulated in many tumors and markedly upregulated in refractory acute leukemia patients compared to sensitive patients (92).

According to the literature we can speculate that; CML cells express miR-320, CML exosomes include enriched miR-320, HNRPA1 selectively sort miR-320 into exosomes, reduced intracellular miR-320 results in resque of BCR/ABL mRNA from degradation, increased antiapoptotic proteins Mcl-1, beta-Catenin, c-Myc, Cyclin D1 and DKK-1 expression in CML cells. Wnt/beta-Catenin signaling pathway is activated. Stabilized beta-Catenin translocate to the nucleus and generate a transcriptional complex with binding to TCF/LEF. miR-320 reduce the expression of beta-Catenin in BMSCs, reduce the maturation of osteoblasts in bone marrow, reduce the expression of osteogenic markers RUNX2, OPN and COL1A1.

6.4.6. Exosomal miR-92a-3p mediated crosstalk

During adipogenesis, several transcription factors including Peroxisome Proliferator-Activated Receptor-gamma (PPAR-gamma) and Cytidine-Cytidine-Adenosine-Adenosine-Thymidine (CCAAT)/Enhancer Binding Family of Proteins (C/EBP) play important roles in adipogenic differentiation of adipose tissue-derived mesenchymal stem cells (AMSCs) (93). Treatment of AMSC with K562-derived exosomes lead to decrease of lipid droplets formation, adipogenic transcription factor C/EBP-alpha mRNA expression and adipocyte-specific markers PPAR-gamma, Fatty Acide Binding Protein 4FABP4 and Adiponectin. miR-92a-3p expression was high in both K562 cells and its exosomes. C/EBP-alpha is one of the target genes of miR-92a-3p and coincubation of ADSCs with miR-92a-3p mimics transfected healthy donor exosomes results in lower adipogenic differentiation (94) However Wang et al., 2008 reported that miR-17-92 cluster members (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, miR-92a) accelerate adipogenetic differentiation in mouse preadipocyte 3T3L1 cell line (95).

7. CONCLUSION REMARKS

Exosomes act as nano vehicles that transport signaling molecules from the CML cells to neighboring cells such as endothelial cells and bone marrow mesenchymal stromal cells. Especially miRNA molecules transported through this way leads to alterations of reciever cells signaling pathways, gene expression pattern surface antigenic properties and protein secretion profiles. Growth factors, cytokines and other factors secreted from exosome reciever cell also act on CML cell characteristics and bone marrow niche. CML derived exosomes and their effects are summarized in Table 1. All of this alterations results in increased survival and growth, chemoresistance development, apoptosis inhibition, decreased adhesion to bone marrow matrix, increased migration and homing of quiescent CML stem cells in the bone marrow matrix in CML cells. This cell-cell communication results in an increase of neoangiogenesis from endothelial cells and suppression of adipogenic and osteoblastic activity and extracellular matrix remodeling through BMSCs. Especially activation of Hedgehog, Notch and Wnt signaling pathways in CML stem cells through cell-cell communication leads to chemoresistance, poor prognosis, recurrence of the disease after the drug discontinuation. It is obvious that there is a necessity for new therapeutic agents in addition to BCR/ABL TKIs to overcome these challenges targeting Hedgehog, Notch, Wnt and autophagy signaling pathways. May be near future loading of drugs, immunomodulator molecules, or miRNA or anti-miRNA transfer vectors into patient derived exosomes or exosomal mimics and targeting them to CML cells may come up as a useful approach to break this cell-cell communication.

Table 1 The effects of CML cell derived exosomal factors on gene expression in target cells
Secreting Cell Exosomal Factor Target Protein Receiver Cell Downregulated Proteins Upregulated Proteins Reference
LAMA84 TGF- beta1 TGFBR LAMA84 BAD BAX PUMA p-SMAD 2/3 p-Akt p-ERK NF-kB BCL-xL BCL2L2 Survivin 45
LAMA84R IL8 IL8R HUVEC - p-Erk½ p-Akt VCAM1 ICAM1 IL8 46
LAMA84 CML patients IL8 IL8R HUVEC Cadherin Beta Catenin p-MAPK p42/44 VCAM-1 ICAM IL8 47
K562 IL8 IL8R HUVEC - p-Src 48
K5621%O2 miR-210 EFNA3 HUVEC EFNA3 - 49
K562 miR-92a ITGA5 HUVEC ITGA5 - 58
LAMA84 miRNA-126 CXCL12 VCAM1 HUVEC CXCL12 VCAM1 - 63
Curcumin treated K562 and LAMA84 miR-21 miR-126b Rho-B MARCKS HUVEC IL8 MARCKSL1 VCAM1 RhoB Membraneous-ZO1 Membraneous-VE-Cadherin 69 68
LAMA84 Not defined Not defined HS5 - IL8 77
Patient Sample ​LAMA84 AREG EGFR HS5 - EGFR SNAIL IL8​ MMP9 ANXA2 79
K562 Not defined Not defined Patient BMSCs sample CXCL12 at 24h Wnt5a at 24h DKK1 at 72h IL6 at 72h TGF-beta at 24h ROS CXCL12 at 48h Wnt5a at 48h DKK1 at 48h IL6 at 48h NO TNF- alpha at 72h 82
K562 miR-711 CD44 BMSCs CD44 - 84
K562 and LAMA84 miR-320 Beta Catenin Patient BMSCs sample ALP RUNX2 Osteopontin OPN COL1A1 CXCL12 KITL - 87
K562 miR-92a-3p C/EBP alpha Patient ADSCs sample C/EBPα PPARγ FABP4 Adiponectin - 94
HUVEC; Human Umbilical Vein Endothelial Cell, BMSCs; Bone Marrow Mesenchymal Stromal Cells; ADSCs; Adipose-Tissue Derived Stem Cells
8. ACKNOWLEDGMENTS

The authors do not declare any conflict of interest.

Abbreviations
AbbreviationExpansion4EBP1

Eukaryotic Translation Initiation Factor 4E-Binding Protein 1

ADAM

A-Disintegrin and Metalloprotease

ANGPT2

Angiopoietin-2

ANXA2

Annexin A2

APC

Adenomatous Polyposis Coli

AREG

Amphiregulin

AXIN

Axis Inhibitor

BAD

BCL2-Associated Agonist of Cell Death

BAX

BCL2-Associated X

BCL2L2

BCL2-Like 2

BCL-xl

BCL2-Related Protein Long Isoform

BCR

Breakpoint Cluster Region

BTC

Betacellulin

C/EBP

CCAAT/Enhancer Binding Proteins

CAT

Catalase

CK1

Creatin Kinase 1

CLDN11

Claudin 11

CML

Chronic Myeloid Leukemia

COL1A1

Collagen Type I, Alpha-1

COX-2

Cyclooxygenase-2

CTO

Carboxyamidotriazole Orotate

CXCL12

Chemokine, CXC Motif, Ligand 12

Delta

Ligand of the Delta-like

Dhh

Desert Hedgehog

DLS

Dynamic Light Scattering

Dvl

Dishevelled

EDN1

Endothelin 1

EDNRB

Endothelin-B Receptor

EFNA3

Ephrin A3

EGF

Epidermal Growth Factor

EGFR

Epidermal Growth Factor Receptor

EPGN

Epithelial Mitogen

EphA2

Ephrin Receptor A2

EREG

Epiregulin

ERK

Extracellular Signal Regulated Kinase

ESCRT

Endosomal Sorting Complexes Required for Transport

FAK

Focal Adhesion Kinase

FDA

Food and Drug Administration

FLT3

FMS-Related Tyrosine Kinase 3

FOXO

Forkhead Box O

Fzd

Frizzled

GAS6

Growth Arrest-Specific 6

G-CSF

Granulocyte-Colony Stimulating Factor

Grb2

Growth Factor Receptor Bound protein 2

GSK-3

Glycogen Synthase Kinase 3

HBEGF

Heparin-Binding EGF-Like Growth Factor

HES

Hairy/Enhancer of Split

HEY

Hairy/Enhancer of Split-Related with YRPW Motif

HGF

Hepatocyte Growth Factor

HIF-1 alpha

Hypoxia Inducible Factor 1 Alpha

HNRNPA1

Heterogeneous Nuclear Ribonucleoprotein A1

HSC70

Heat-Shock Cognate Protein 70

HSP90

Heat Shock Protein 90

ICAM-1

Intercellular Adhesion Molecule-1

IGFBP2

Insulin-like Growth Factor Binding Protein 2

PITPNC1

Phosphatidylinositol Transfer Protein Cytoplasmic 1

Ihh

Indian Hedgehog

ITGA5

Integrin α5

JAG

Jagged

JAK

Janus Kinase

JNK

c-Jun N-terminal Kinase

Klf4

Krueppel-Like Factor 4

LRP5/6

Low-Density Lipoprotein Receptor-Related Protein

MAML1-3

Mastermind-Like

MARCKSL1

MARCKS-Like Protein 1

MERTK

c-Mer Tyrosine Kinase

MMP9

Matrix Metalloproteinase 9

MnSOD

Manganese Superoxide Dismutase

mSIN1

SAPK Interacting Protein 1

mTOR

Mammalian Target of Rapamycin

NECD

Notch Extracellular Domain

NF-kB

Nuclear Factor-kappa B

NICD

Notch Intracellular Domain

NO

Nitric Oxide

NOD/SCID

Non Obese Diabetic/ Severe Combine Immudodeficient

NRG

Neuregulin

NRP1

Neuropilin-1

nSMase

Sphingomyelinase

NTA

Nanoparticle Tracking Analysis

OPN

Osteopontin

OSCC

Oral Squamous Cell Carcinoma

PDGF-BB

Platellet-Derived Growth Factor BB

PDGFR

Platelet-Derived Growth Factor Receptor

PDK1

Phosphoinositide‐Dependent Kinase 1

Ph

Philadelphia

PI3K

Phosphatydylinositol 3-Kinase

PIP2

Phosphatidylinositol 4,5‐bisphosphate

PIP3

Phosphatidylinositol 3,4,5‐trisphosphate

PITPNC1

Phosphatidylinositol Transfer Protein Cytoplasmic 1

PP2A

Protein Phosphatase 2A

PPARγ

Peroxisome Proliferator-Activated Receptor-γ

Prop1

Paired Like Homeobox-1

Protor

Protein Observed with Rictor1

PS

Presenilin

Ptc

Patched1

PTEN

Phosphatase and Tensin Homologue

PUMA

p53-Upregulated Modulator of Apoptosis

RAPTOR

Regulatory Associated Protein of mTOR

RBPJ

Recombination Signal-Binding Protein for Immunoglobulin Kappa J Region

RET

Rearranged During Transfection

Rheb

Ras Homolog Enriched in Brain

RhoB

Ras Homolog Gene Family Member B

RICTOR

Rapamycin-Insensitive Companion of mTOR

rpS6

S6 Ribosomal Protein

RUNX2

Runt-Related Transcription Factor 2

S6K

S6 Kinase

SEM

Scanning Electron Microscopy

Shh

Sonic Hedgehog

sKITL

Kit Ligand

SMAD

Sma-and Mad-Related Protein

Smo

Smoothened

SOS

Son of Sevenless

STAT

Signal Transducer and Activator of Transcription

TEM

Transmission Electron Microscopy

TGF

Transforming Growth Factor

THBS1

Thrombospondin 1

TIMP-1

Tissue Inhibitor of Metalloproteinase 1

TKIs

Tyrosine Kinase Inhibitors

TNF-alpha

Tumor Necrosis Factor Alpha

tRPS

Tunable Resistive Pulse Sensing

TSC

Tuberous Sclerosis

TSG101

Tumor Susceptibility Gene 101

VCAM1

Vascular Cell Adhesion Molecule 1

VEGF

Vascular Endothelial Growth Factor

VEGFR

Vascular Endothelial Growth Factor Receptor

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