Leukemia stem cells: the root of chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a chromosome translocation that generates the Bcr-Abl oncogene encoding a constitutive kinase activity. Despite remarkable success in controlling CML at chronic phase by Bcr-Abl tyrosine kinase inhibitors (TKIs), a significant proportion of CML patients treated with TKIs develop drug resistance due to the inability of TKIs to kill leukemia stem cells (LSCs) that are responsible for initiation, drug resistance, and relapse of CML. Therefore, there is an urgent need for more potent and safer therapies against leukemia stem cells for curing CML. A number of LSCassociated targets and corresponding signaling pathways, including CaMKII-γ, a critical molecular switch for co-activating multiple LSC-associated signaling pathways, have been identified over the past decades and various small inhibitors targeting LSC are also under development. Increasing evidence shows that leukemia stem cells are the root of CML and targeting LSC may offer a curable treatment option for CML patients. This review summarizes the molecular biology of LSC and itsassociated targets, and the potential clinical application in chronic myeloid leukemia.

Keywords

chronic myeloid leukemia (CML) / leukemia stem cells (LSCs) / tyrosine kinase inhibitors (TKIs) / CaMKII-γ / molecular switch

References

[1] Adamia S, Pilarski PM, Bar-Natan M, Stone RM, Griffin JD (2013) Alternative splicing in chronic myeloid leukemia (CML): a novel therapeutic target. Curr Cancer Drug Targets13: 735-748

[2] Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A100: 3983-3988

[3] Ang ES, Zhang P, Steer JH, Tan JW, Yip K, Zheng MH, Joyce DA, Xu J (2007) Calcium/calmodulin-dependent kinase activity is required for efficient induction of osteoclast differentiation and bone resorption by receptor activator of nuclear factor kappa B ligand (RANKL). J Cell Physiol212: 787-795

[4] Barnes DJ, Melo JV (2006) Primitive, quiescent and difficult to kill: the role of non-proliferating stem cells in chronic myeloid leukemia. Cell cycle (Georgetown, Tex.)5: 2862-2866

[5] Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ (1994) Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood83: 2038-2044

[6] Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL, Arber DA, Slovak ML, Forman SJ (2003) Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood101: 4701-4707

[7] Bhattacharyya J, Mihara K, Yasunaga S, Tanaka H, Hoshi M, Takihara Y, Kimura A (2009) BMI-1 expression is enhanced through transcriptional and posttranscriptional regulation during the progression of chronic myeloid leukemia. Ann Hematol88: 333-340

[8] Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA (1996) A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med184: 1101-1109

[9] Bouallegue A, Pandey NR, Srivastava AK (2009) CaMKII knockdown attenuates H2O2-induced phosphorylation of ERK1/2, PKB/Akt, and IGF-1R in vascular smooth muscle cells. Free Radical Biol Med47: 858-866

[10] Brooks CL, Gu W (2009) How does SIRT1 affect metabolism, senscence and cancer? Nat Rev Cancer9: 123-128

[11] Cao R, Tsukada Y, Zhang Y (2005) Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell20: 845-854

[12] Cashman J, Clark-Lewis I, Eaves A, Eaves C (2002) Stromal-derived factor 1 inhibits the cycling of very primitive human hematopoietic cells in vitro and in NOD/SCID mice. Blood99: 792-799

[13] Chang JS, Santhanam R, Trotta R, Neviani P, Eiring AM, Briercheck E, Ronchetti M, Roy DC, Calabretta B, Caligiuri MA, Perrotti D (2007) High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalphadriven myeloid differentiation. Blood110: 994-1003

[14] Chen XS, Sheller JR, Johnson EN, Funk CD (1994) Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene. Nature372: 179-182

[15] Chu S, Xu H, Shah NP, Snyder DS, Forman SJ, Sawyers CL, Bhatia R (2005) Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood105: 2093-2098

[16] Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, Barow M, Mountford JC, Holyoake TL (2006) Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood107: 4532-4539

[17] Cramer K, Nieborowska-Skorska M, Koptyra M, Slupianek A, Penserga ET, Eaves CJ, Aulitzky W, Skorski T (2008) BCR/ ABL and other kinases from chronic myeloproliferative disorders stimulate single-strand annealing, an unfaithful DNA doublestrand break repair. Cancer Res68: 6884-6888

[18] Culjkovic B, Borden KL (2009) Understanding and targeting the eukaryotic translation initiation factor eIF4E in head and neck cancer. J Oncol2009: 981679

[19] Dash AB, Williams IR, Kutok JL, Tomasson MH, Anastasiadou E, Lindahl K, Li S, Van Etten RA, Borrow J, Housman D, Druker B, Gilliland DG (2002) A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Natl Acad Sci U S A99: 7622-7627

[20] Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, Trussell C, Schmitt-Graeff A, Landwerlin K, Veelken H, Warmuth M (2008) Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell14: 238-249

[21] Druker BJ (2008) Translation of the Philadelphia chromosome into therapy for CML. Blood112: 4808-4817

[22] Eaves C, Cashman J, Eaves A (1998) Defective regulation of leukemic hematopoiesis in chronic myeloid leukemia. Leuk Res22: 1085-1096

[23] Esteller M (2008) Epigenetics in cancer. N Engl J Med358: 1148-1159

[24] Gallipoli P, Pellicano F, Morrison H, Laidlaw K, Allan EK, Bhatia R, Copland M, Jorgensen HG, Holyoake TL (2013) Autocrine TNFalpha production supports CML stem and progenitor cell survival and enhances their proliferation. Blood122: 3335-3339

[25] Gallipoli P, Cook A, Rhodes S, Hopcroft L, Wheadon H, Whetton AD, Jorgensen HG, Bhatia R, Holyoake TL (2014) JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood124: 1492-1501

[26] Gerber JM, Gucwa JL, Esopi D, Gurel M, Haffner MC, Vala M, Nelson WG, Jones RJ, Yegnasubramanian S (2013) Genomewide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations. Oncotarget4: 715-728

[27] Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL (2002) Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood99: 319-325

[28] Gu Y, Chen T, Meng Z, Gan Y, Xu X, Lou G, Li H, Gan X, Zhou H, Tang J, Xu G, Huang L, Zhang X, Fang Y, Wang K, Zheng S, Huang W, Xu R (2012) CaMKII gamma, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine. Blood120: 4829-4839

[29] Guzman ML, Rossi RM, Karnischky L, Li X, Peterson DR, Howard DS, Jordan CT (2005) The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood105: 4163-4169

[30] Guzman ML, Li X, Corbett CA, Rossi RM, Bushnell T, Liesveld JL, Hebert J, Young F, Jordan CT (2007) Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8). Blood110: 4436-4444

[31] Hamdy MS, El-Haddad AM, Bahaa ENM, Makhlouf MM, Abdel- Hamid SM (2011) RAD51 and XRCC3 gene polymorphisms and the risk of developing acute myeloid leukemia. J Investig Med59: 1124-1130

[32] Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK (1998) Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A95: 4607-4612

[33] Hojabrpour P, Waissbluth I, Ghaffari M, Cox ME, Duronio V (2012) CaMKII-gamma mediates phosphorylation of BAD at Ser170 to regulate cytokine-dependent survival and proliferation. Biochem442: 139-149

[34] Holtz MS, Slovak ML, Zhang F, Sawyers CL, Forman SJ, Bhatia R (2002) Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood99: 3792-3800

[35] Holyoake T, Jiang X, Eaves C, Eaves A (1999) Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood94: 2056-2064

[36] Hu Y, Chen Y, Douglas L, Li S (2009) beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia23: 109-116

[37] Hughes K, Edin S, Antonsson A, Grundstrom T (2001) Calmodulindependent kinase II mediates T cell receptor/CD3- and phorbol ester-induced activation of IkappaB kinase. J Biol Chem276: 36008-36013

[38] Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J, Pandolfi PP (2008) PML targeting eradicates quiescent leukaemia-initiating cells. Nature453: 1072-1078

[39] Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL (2004a) Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med351: 657-667

[40] Jamieson CH, Weissman IL, Passegue E (2004b) Chronic versus acute myelogenous leukemia: a question of self-renewal. Cancer Cell6: 531-533

[41] Jiang X, Saw KM, Eaves A, Eaves C (2007) Instability of BCR-ABL gene in primary and cultured chronic myeloid leukemia stem cells. J Natl Cancer Inst99: 680-693

[42] Jones PA, Baylin S (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet3: 415-428

[43] Jorgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL (2007) Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood109: 4016-4019

[44] Kabarowski JH, Witte ON (2000) Consequences of BCR-ABL expression within the hematopoietic stem cell in chronic myeloid leukemia. Stem Cells18: 399-408

[45] Kaminska J, Klimczak-Jajor E, Bany-Laszewicz U (2008) Src kinases in the process of maturation megakryocyte progenitors. Postepy Biochem54: 378-383

[46] Karanes C, Nelson GO, Chitphakdithai P, Agura E, Ballen KK, Bolan CD, Porter DL, Uberti JP, King RJ, Confer DL (2008) Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant14: 8-15

[47] Kaspar R, Rychlik W, White MW, Rhoads RE, Morris DR (1990) Simultaneous cytoplasmic redistribution of ribosomal protein L32 mRNA and phosphorylation of eukaryotic initiation factor 4E after mitogenic stimulation of Swiss 3T3 cells. J Biol Chem265: 3619-3622

[48] Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, Szydlo R, Olavarria E, Kaeda J, Goldman JM, Marin D (2008) Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol26: 4806-4813

[49] Kortesidis A, Zannettino A, Isenmann S, Shi S, Lapidot T, Gronthos S (2005) Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood105: 3793-3801

[50] Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg A-M, Sauvageau G (1998) Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO17: 3714-3725

[51] Li L, Wang L, Li L, Wang Z, Ho Y, McDonald T (2012) Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell21: 266-281

[52] Lim S, Saw TY, Zhang M, Janes MR, Nacro K, Hill J, Lim AQ, Chang CT, Fruman DA, Rizzieri DA (2013) Targeting of the MNKeIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc Natl Acad Sci U S A. 110: E2298-E2307

[53] Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature411: 375-379

[54] Liu X, Rubin JS, Kimmel AR (2005) Rapid, Wnt-induced changes in GSK3beta associations that regulate beta-catenin stabilization are mediated by Galpha proteins. Curr Biol15: 1989-1997

[55] Liu X, Yao M, Li N, Wang C, Zheng Y, Cao X (2008) CaMKII promotes TLR-triggered proinflammatory cytokine and type I interferon production by directly binding and activating TAK1 and IRF3 in macrophages. Blood112: 4961-4970

[56] Liu X, Duan B, Cheng Z, Jia X, Mao L, Fu H, Che Y, Ou L, Liu L, Kong D (2011) SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion. Protein Cell2: 845-854

[57] Lowe SW, Sherr CJ (2003) Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev13: 77-83

[58] Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W (2001) Negative control of p53 by Sir2 alpha promotes cell survival under stress. Cell107: 137-148

[59] Marganski WA, Gangopadhyay SS, Je HD, Gallant C, Morgan KG (2005) Targeting of a novel Ca+ 2/calmodulin-dependent protein kinase II is essential for extracellular signal-regulated kinasemediated signaling in differentiated smooth muscle cells. Circ Res97: 541-549

[60] Marino MW, Pfeffer LM, Guidon PT, Donner DB (1989) Tumornecrosis factor induces phosphorylation of a 28kd mRNA cap-binding protein in human cervical carcinoma cells. Proc Natl Acad Sci U S A86: 8417-8421

[61] Mohty M, Yong AS, Szydlo RM, Apperley JF, Melo JV (2007) The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. Blood110: 380-383

[62] Mohty M, Szydlo RM, Yong AS, Apperley JF, Goldman JM, Melo JV (2008) Association between BMI-1 expression, acute graftversus-host disease, and outcome following allogeneic stem cell transplantation from HLA-identical siblings in chronic myeloid leukemia. Blood112: 2163-2166

[63] Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev19: 1432-1437

[64] Momparler RL, Idaghdour Y, Marquez VE, Momparler LF (2012) Synergistic antileukemic action of a combination of inhibitors of DNA methylation and histone methylation. Leuk Res36: 1049-1054

[65] Morrison SJ, Uchida N, Weissman IL (1995) The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol11: 35-71

[66] Naiyer AJ, Jo DY, Ahn J, Mohle R, Peichev M, Lam G, Silverstein RL, Moore MA, Rafii S (1999) Stromal derived factor-1-induced chemokinesis of cord blood CD34(+) cells (long-term cultureinitiating cells) through endothelial cells is mediated by E-selectin. Blood94: 4011-4019

[67] Neering SJ, Bushnell T, Sozer S, Ashton J, Rossi RM, Wang PY, Bell DR, Heinrich D, Bottaro A, Jordan CT (2007) Leukemia stem cells in a genetically defined murine model of blast-crisis CML. Blood110: 2578-2585

[68] Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, Mao H, Chang JS, Galietta A, Uttam A, Roy DC, Valtieri M, Bruner- Klisovic R, Caligiuri MA, Bloomfield CD, Marcucci G, Perrotti D (2005) The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABLregulated SET protein. Cancer Cell8: 355-368

[69] Neviani P, Harb JG, Oaks JJ, Santhanam R, Walker CJ, Ellis JJ, Ferenchak G, Dorrance AM, Paisie CA, Eiring AM, Ma Y, Mao HC, Zhang B, Wunderlich M, May PC, Sun C, Saddoughi SA, Bielawski J, Blum W, Klisovic RB, Solt JA, Byrd JC, Volinia S, Cortes J, Huettner CS, Koschmieder S, Holyoake TL, Devine S, Caligiuri MA, Croce CM, Garzon R, Ogretmen B, Arlinghaus RB, Chen CS, Bittman R, Hokland P, Roy DC, Milojkovic D, Apperley J, Goldman JM, Reid A, Mulloy JC, Bhatia R, Marcucci G, Perrotti D (2013) PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Invest123: 4144-4157

[70] Niemann CU, Kjeldsen L, Ralfkiaer E, Jensen MK, Borregaard N (2007) Serglycin proteoglycan in hematologic malignancies: a marker of acute myeloid leukemia. Leukemia21: 2406-2410

[71] Nowell PC, Hungerford DA (1960) Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst25: 85-109

[72] Olsson B, Legros L, Guilhot F, Stromberg K, Smith J, Livesey FJ, Wilson DH, Zetterberg H, Blennow K (2014) Imatinib treatment and Abeta42 in humans. Alzheimers Dement10: S374-S380

[73] Passegue E, Jochum W, Schorpp-Kistner M, Mohle-Steinlein U, Wagner EF (2001) Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineage. Cell104: 21-32

[74] Peng H, Wu Y, Duan Z, Ciborowski P, Zheng JC (2012) Proteolytic processing of SDF-1alpha by matrix metalloproteinase-2 impairs CXCR4 signaling and reduces neural progenitor cell migration. Protein Cell3: 875-882

[75] Quaiser T, Anton R, Kuhl M (2006) Kinases and G proteins join the Wnt receptor complex. BioEssays28: 339-343

[76] Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414: 105-111

[77] Rezvani K, Price DA, Brenchley JM, Kilical Y, Gostick E, Sconocchia G, Hansmann K, Kurlander R, Douek DC, Barrett AJ (2007) Transfer of PR1-specific T-cell clones from donor to recipient by stem cell transplantation and association with GvL activity. Cytotherapy9: 245-251

[78] Rowley JD (1973) Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature243: 290-293

[79] Saudy NS, Fawzy IM, Azmy E, Goda EF, Eneen A, Abdul SEM (2014) BMI1 gene expression in myeloid leukemias and its impact on prognosis. Blood Cells Mol Dis53: 194-198

[80] Scheller M, Schonheit J, Zimmermann K, Leser U, Rosenbauer F, Leutz A (2013) Cross talk between Wnt/beta-catenin and Irf8 in leukemia progression and drug resistance. J Exp Med210: 2239-2256

[81] Sengupta A, Banerjee S (2007) Pleiotropic p27 (Kip1), BCR-ABL and leukemic stem cell: the trio in concert. Leukemia21: 2559-2561

[82] Shen WF, Rozenfeld S, Kwong A, Kom ves LG, Lawrence HJ, Largman C (1999) HOXA9 forms triple complexes with PBX2 and MEIS1 in myeloid cells. Mol Cell Biol19: 3051-3061

[83] Si J, Collins SJ (2008) Activated Ca2+/calmodulin-dependent protein kinase IIgamma is a critical regulator of myeloid leukemia cell proliferation. Cancer Res68: 3733-3742

[84] Si J, Mueller L, Collins SJ (2007) CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells. J Clin Invest117: 1412-1421

[85] Siddiqui N, Borden KL (2012) mRNA export and cancer. Wiley Interdisciplinary Rev RNA3: 13-25

[86] Slupianek A, Falinski R, Znojek P, Stoklosa T, Flis S, Doneddu V, Pytel D, Synowiec E, Blasiak J, Bellacosa A, Skorski T (2013) BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability. Leukemia27: 629-634

[87] Sorel N, Bonnet ML, Guillier M, Guilhot F, Brizard A, Turhan AG (2004) Evidence of ABL-kinase domain mutations in highly purified primitive stem cell populations of patients with chronic myelogenous leukemia. Biochem Biophys Res Commun323: 728-730

[88] Strathdee G, Holyoake TL, Sim A, Parker A, Oscier DG, Melo JV, Meyer S, Eden T, Dickinson AM, Mountford JC, Jorgensen HG, Soutar R, Brown R (2007) Inactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis. Clin Cancer Res13: 5048-5055

[89] Tauchi T, Boswell HS, Leibowitz D, Broxmeyer HE (1994) Coupling between p210bcr-abl and Shc and Grb2 adaptor proteins in hematopoietic cells permits growth factor receptor-independent link to ras activation pathway. J Exp Med179: 167-175

[90] Timmins JM, Ozcan L, Seimon TA, Li G, Malagelada C, Backs J, Backs T, Bassel-Duby R, Olson EN, Anderson ME, Tabas I (2009) Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. J Clin Invest119: 2925-2941

[91] Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M (2004) Stem cells and cancer; the polycomb connection. Cell 118: 409-418

[92] Wang Y, Cai D, Brendel C, Barett C, Erben P, Manley PW, Hochhaus A, Neubauer A, Burchert A (2007) Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood109: 2147-2155

[93] Wang Z, Yuan H, Roth M, Stark JM, Bhatia R, Chen WY (2013) SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells. Oncogene32: 589-598

[94] Weissman IL (2000) Stem cells: units of development, units of regeneration, and units in evolution. Cell100: 157-168

[95] Williams DA, Zheng Y, Cancelas JA (2008) Rho GTPases and regulation of hematopoietic stem cell localization. Methods Enzymol439: 365-393

[96] Wodarz D (2008) Stem cell regulation and the development of blast crisis in chronic myeloid leukemia: implications for the outcome of Imatinib treatment and discontinuation. Med Hypotheses70: 128-136

[97] Yang ZF, Zhang H, Ma L, Peng C, Chen Y, Wang J, Green MR, Li S, Rosmarin AG (2013) GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2. Proc Natl Acad Sci U S A110: 2312-2317

[98] Yong AS, Keyvanfar K, Eniafe R, Savani BN, Rezvani K, Sloand EM, Goldman JM, Barrett AJ (2008) Hematopoietic stem cells and progenitors of chronic myeloid leukemia express leukemiaassociated antigens: implications for the graft-versus-leukemia effect and peptide vaccine-based immunotherapy. Leukemia22: 1721-1727

[99] Zhang B, Ho YW, Huang Q, Maeda T, Lin A, Lee SU, Hair A, Holyoake TL, Huettner C, Bhatia R (2012) Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell21: 577-592

[100] Zhao L, Moos MP, Grabner R, Pedrono F, Fan J, Kaiser B, John N, Schmidt S, Spanbroek R, Lotzer K, Huang L, Cui J, Rader DJ, Evans JF, Habenicht AJ, Funk CD (2004) The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med10: 966-973

[101] Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, Munchhof M, VanArsdale T, Beachy PA, Reya T (2009) Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature458: 776-779

[102] Zhu J, Zhou L, Wu G, Konig H, Lin X, Li G, Qiu XL, Chen CF, Hu CM, Goldblatt E, Bhatia R, Chamberlin AR, Chen PL, Lee WH (2013) A novel small molecule RAD51 inactivator overcomes imatinibresistance in chronic myeloid leukaemia. EMBO Mol Med5: 353-365

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