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Chronic myelogenous leukemia

Declaration of Bcr-Abl1 independence

Leukemia volume 34, pages 2827–2836 (2020)Cite this article

Subjects

Starting with imatinib, BCR-ABL1 tyrosine kinase inhibitors (TKIs) have changed the face of chronic myeloid leukemia (CML). Patients diagnosed with chronic phase (CP) CML who have access to appropriate health care resources have a life span almost equal to that of age-matched controls, and their survival is driven by comorbidities [1, 2]. Despite this progress, TKI resistance remains a challenge, and there are still more than 1000 CML-related deaths annually in the US (Surveillance, Epidemiology, and End Results (SEER), accessed 03/13/20). Of those patients responding to TKIs, at least two-thirds are expected to require continuous TKI therapy to avoid recurrence of active CML, indicating that fully leukemogenic CML cells survive despite the suppression of BCR-ABL1 kinase activity over years. This suggests that the survival of these cells is independent of BCR-ABL1 kinase activity. The term ‘persistence’ is frequently used to describe this state of low-level residual CML. At the opposite end of the clinical spectrum is blast phase CML (BP-CML), where deep responses to TKIs are rare, and resistance after a transient remission is the rule. BCR-ABL1 kinase domain mutations readily explain resistance in many of these patients, but a substantial proportion of cases lack ‘explanatory mutations’, indicating that the TKI resistant BP-CML cells have activated alternative growth and survival pathways. Thus, although we tend to think of CML as a disease driven by BCR-ABL1 kinase activity, cells at the extremes of the clinical spectrum exhibit partial or complete BCR-ABL1 independence. Here we aim to develop a unifying concept of BCR-ABL1 independence, hoping to stimulate discussion and inform research directions. Although it is a widely held impression that CML is a problem of the past, the adverse events and high costs associated with life-long TKI therapy are clear indication that the job is not finished. We argue that understanding BCR-ABL1 independence in CML is the key to making progress [3].

The terms describing various scenarios of TKI resistance are not always used in a consistent manner. For the purpose of the present manuscript, primary resistance denotes the failure to achieve a predefined level of response, typically a complete hematologic response, complete cytogenetic response, major molecular response (MMR), or deep molecular response [4]. Acquired resistance is the loss of a given response or the progression to accelerated or blast phase CML while on TKI therapy. Persistence denotes the presence of low-level residual leukemia in patients responding to TKIs, either detectable during TKI therapy or inferred by recurrence after TKI discontinuation. It is important to distinguish between resistance (increasing disease activity on TKI therapy) and recurrence (increasing disease activity after discontinuation of TKI therapy), as their biology is quite different.

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Fig. 1: Molecular responses over time in phase 3 studies of newly diagnosed chronic phase CML patients.
Fig. 2: Evolutionary pathways in CHIP, CP-CML, BP-CML, and AML.
Fig. 3: BCR-ABL1 dependence and independence in CML.
Fig. 4: Factors contributing to BCR-ABL1-independent tyrosine kinase inhibitor resistance.

References

  1. Saussele S, Krauss M-P, Hehlmann R, Lauseker M, Proetel U, Kalmanti L, et al. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV. Blood. 2015;126:42–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103:553–61.

    CAS  PubMed  Google Scholar 

  3. Saglio G, Gale RP. Prospects for achieving treatment-free remission in chronic myeloid leukaemia. Br J Haematol. 2020;190:318–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–80.

    CAS  PubMed  Google Scholar 

  6. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2:117–25.

    CAS  PubMed  Google Scholar 

  7. O’Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood. 2007;110:2242–9.

    PubMed  Google Scholar 

  8. Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000;96:1070–9.

    CAS  PubMed  Google Scholar 

  9. Chandran RK, Geetha N, Sakthivel KM, Aswathy CG, Gopinath P, Raj TVA, et al. Genomic amplification of BCR-ABL1 fusion gene and its impact on the disease progression mechanism in patients with chronic myelogenous leukemia. Gene. 2019;686:85–91.

    CAS  PubMed  Google Scholar 

  10. Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–6.

    CAS  PubMed  Google Scholar 

  11. Giustacchini A, Thongjuea S, Barkas N, Woll PS, Povinelli BJ, Booth CAG, et al. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat Med. 2017;23:692–702.

    CAS  PubMed  Google Scholar 

  12. Eadie LN, Dang P, Saunders VA, Yeung DT, Osborn MP, Grigg AP, et al. The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment. Leukemia. 2017;31:75–82.

    CAS  PubMed  Google Scholar 

  13. Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368–73.

    CAS  PubMed  Google Scholar 

  14. Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J, et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2008;112:2024–7.

    CAS  PubMed  Google Scholar 

  15. Qiang W, Antelope O, Zabriskie MS, Pomicter AD, Vellore NA, Szankasi P, et al. Mechanisms of resistance to the BCR-ABL1 allosteric inhibitor asciminib. Leukemia. 2017;31:2844–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Eadie LN, Saunders VA, Branford S, White DL, Hughes TP. The new allosteric inhibitor asciminib is susceptible to resistance mediated by ABCB1 and ABCG2 overexpression in vitro. Oncotarget. 2018;9:13423–37.

    PubMed  PubMed Central  Google Scholar 

  17. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824–30.

    CAS  PubMed  Google Scholar 

  18. Ramaraj P, Singh H, Niu N, Chu S, Holtz M, Yee JK, et al. Effect of mutational inactivation of tyrosine kinase activity on BCR/ABL-induced abnormalities in cell growth and adhesion in human hematopoietic progenitors. Cancer Res. 2004;64:5322–31.

    CAS  PubMed  Google Scholar 

  19. Agarwal A, Mackenzie RJ, Besson A, Jeng S, Carey A, LaTocha DH, et al. BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein. Blood. 2014;124:3260–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet. 2009;41:783–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Neviani P, Harb JG, Oaks JJ, Santhanam R, Walker CJ, Ellis JJ, et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Investig. 2013;123:4144–57.

    CAS  PubMed  Google Scholar 

  22. Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12:528–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jamieson CHM, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl J Med. 2004;351:657–67.

    CAS  PubMed  Google Scholar 

  24. Dolinska M, Piccini A, Wong WM, Gelali E, Johansson A-S, Klang J, et al. Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34(+)CD38(-) stem and progenitor cells in chronic myeloid leukemia. Biochem Biophys Res Commun. 2017;490:378–84.

    CAS  PubMed  Google Scholar 

  25. Schürch C, Riether C, Matter MS, Tzankov A, Ochsenbein AF. CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression. J Clin Investig. 2012;122:624–38.

    PubMed  Google Scholar 

  26. Coluccia AML, Vacca A, Duñach M, Mologni L, Redaelli S, Bustos VH, et al. Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 2007;26:1456–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Eiring AM, Khorashad JS, Anderson DJ, Yu F, Redwine HM, Mason CC, et al. β-Catenin is required for intrinsic but not extrinsic BCR-ABL1 kinase-independent resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. Leukemia. 2015;29:2328–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. O’Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012;12:513–26.

    PubMed  Google Scholar 

  29. O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401–12.

    PubMed  PubMed Central  Google Scholar 

  30. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N. Engl J Med. 2012;367:2075–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. lancet Oncol. 2016;17:612–21.

    CAS  PubMed  Google Scholar 

  32. Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N. Engl J Med. 2019;381:2315–26.

    CAS  PubMed  Google Scholar 

  33. Wylie AA, Schoepfer J, Jahnke W, Cowan-Jacob SW, Loo A, Furet P, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543:733–7.

    CAS  PubMed  Google Scholar 

  34. Raimondi C, Fantin A, Lampropoulou A, Denti L, Chikh A, Ruhrberg C. Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1-dependent ABL1 activation in endothelial cells. J Exp Med. 2014;211:1167–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Latifi Y, Moccetti F, Wu M, Xie A, Packwood W, Qi Y, et al. Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib. Blood. 2019;133:1597–606.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hadzijusufovic E, Albrecht-Schgoer K, Huber K, Hoermann G, Grebien F, Eisenwort G, et al. Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site. Leukemia. 2017;31:2388–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol. 2015;33:4210–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Burslem GM, Schultz AR, Bondeson DP, Eide CA, Savage Stevens SL, Druker BJ, et al. Targeting BCR-ABL1 in chronic myeloid leukemia by PROTAC-mediated targeted protein degradation. Cancer Res. 2019;79:4744–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Pagani IS, Dang P, Saunders VA, Grose R, Shanmuganathan N, Kok CH, et al. Lineage of measurable residual disease in patients with chronic myeloid leukemia in treatment-free remission. Leukemia. 2019. https://doi.org/10.1038/s41375-019-0647-x.

  40. Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35.

    CAS  PubMed  Google Scholar 

  41. Ilander M, Olsson-Strömberg U, Schlums H, Guilhot J, Brück O, Lähteenmäki H, et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017;31:1108–16.

    CAS  PubMed  Google Scholar 

  42. Schütz C, Inselmann S, Saussele S, Dietz CT, Mu Ller MC, Eigendorff E, et al. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Leukemia. 2017;31:829–36.

    PubMed  Google Scholar 

  43. Irani YD, Hughes A, Clarson J, Kok CH, Shanmuganathan N, White DL, et al. Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells. Br J Haematol. 2020. https://doi.org/10.1111/bjh.16718. [epub ahead of print].

  44. Hughes A, Yong ASM. Immune effector recovery in chronic myeloid leukemia and treatment-free remission. Front Immunol. 2017;8:469.

    PubMed  PubMed Central  Google Scholar 

  45. Pastushenko I, Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 2019;29:212–26.

    CAS  PubMed  Google Scholar 

  46. Yuan S, Norgard RJ, Stanger BZ. Cellular plasticity in cancer. Cancer Discov. 2019;9:837–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Patel AB, O’Hare T, Deininger MW. Mechanisms of resistance to ABL kinase inhibition in chronic myeloid leukemia and the development of next generation ABL kinase inhibitors. Hematol Oncol Clin North Am. 2017;31:589–612.

    PubMed  PubMed Central  Google Scholar 

  48. Loriaux M, Deininger M. Clonal cytogenetic abnormalities in Philadelphia chromosome negative cells in chronic myeloid leukemia patients treated with imatinib. Leuk Lymphoma. 2004;45:2197–203.

    CAS  PubMed  Google Scholar 

  49. Mauro MJ. Defining and managing imatinib resistance. Hematology Am Soc Hematol Educ Program. 2006:219–25.

  50. Kumari A, Brendel C, Hochhaus A, Neubauer A, Burchert A. Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib. Blood. 2012;119:530–9.

    CAS  PubMed  Google Scholar 

  51. Karpas A, Fischer P, Swirsky D. Human myeloma cell line carrying a Philadelphia chromosome. Science. 1982;216:997–9.

    CAS  PubMed  Google Scholar 

  52. Lugo TG, Witte ON. The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. Mol Cell Biol. 1989;9:1263–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Daley GQ, McLaughlin J, Witte ON, Baltimore D. The CML-specific P210 bcr/abl protein, unlike v-abl, does not transform NIH/3T3 fibroblasts. Science. 1987;237:532–5.

    CAS  PubMed  Google Scholar 

  54. Branford S, Wang P, Yeung DT, Thomson D, Purins A, Wadham C, et al. Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease. Blood. 2018;132:948–61.

    CAS  PubMed  Google Scholar 

  55. Ko TK, Javed A, Lee KL, Pathiraja TN, Liu X, Malik S, et al. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood. 2020;135:2337–53.

    PubMed  Google Scholar 

  56. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2006;103:2794–9.

    CAS  PubMed  Google Scholar 

  57. McWeeney SK, Pemberton LC, Loriaux MM, Vartanian K, Willis SG, Yochum G, et al. A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood. 2010;115:315–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R, et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101:690–8.

    CAS  PubMed  Google Scholar 

  59. Wu J, Meng F, Lu H, Kong L, Bornmann W, Peng Z, et al. Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood. 2008;111:3821–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Ma L, Shan Y, Bai R, Xue L, Eide CA, Ou J, et al. A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia. Sci Transl Med. 2014;6:252ra121.

  61. Esposito N, Colavita I, Quintarelli C, Sica AR, Peluso AL, Luciano L, et al. SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia. Blood. 2011;118:3634–44.

    CAS  PubMed  Google Scholar 

  62. Mitchell R, Hopcroft LEM, Baquero P, Allan EK, Hewit K, James D, et al. Targeting BCR-ABL-independent TKI resistance in chronic myeloid leukemia by mTOR and autophagy inhibition. J Natl Cancer Inst. 2018;110:467–78.

    CAS  PubMed  Google Scholar 

  63. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell. 2005;8:355–68.

    CAS  PubMed  Google Scholar 

  64. Lucas CM, Harris RJ, Giannoudis A, Copland M, Slupsky JR, Clark RE. Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression. Blood. 2011;117:6660–8.

    CAS  PubMed  Google Scholar 

  65. Eiring AM, Khorashad JS, Anderson DJ, Yu F, Redwine HM, Mason CC, et al. Beta-Catenin is required for intrinsic but not extrinsic BCR-ABL1 kinase-independent resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. Leukemia. 2015;29:2328–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-β-catenin signaling. Blood. 2013;121:1824–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Heidel FH, Bullinger L, Feng Z, Wang Z, Neff TA, Stein L, et al. Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell. 2012;10:412–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Walz C, Ahmed W, Lazarides K, Betancur M, Patel N, Hennighausen L, et al. Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. Blood. 2012;119:3550–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Traer E, MacKenzie R, Snead J, Agarwal A, Eiring AM, O’Hare T, et al. Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia. 2012;26:1140–3.

    CAS  PubMed  Google Scholar 

  70. Bewry NN, Nair RR, Emmons MF, Boulware D, Pinilla-Ibarz J, Hazlehurst LA. Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol Cancer Ther. 2008;7:3169–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Wang Y, Cai D, Brendel C, Barett C, Erben P, Manley PW, et al. 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. Blood. 2007;109:2147–55.

    CAS  PubMed  Google Scholar 

  72. Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Heidel FH, Bullinger L, Feng Z, Wang Z, Neff TA, Stein L, et al. Genetic and pharmacologic inhibition of beta-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell. 2012;10:412–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Lim S, Saw TY, Zhang M, Janes MR, Nacro K, Hill J, et al. Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc Natl Acad Sci USA. 2013;110:E2298–307.

    CAS  PubMed  Google Scholar 

  75. Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-beta-catenin signaling. Blood. 2013;121:1824–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Agarwal P, Zhang B, Ho Y, Cook A, Li L, Mikhail FM, et al. Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine acyltransferase in combination with TKI. Blood. 2017;129:1008–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010;463:501–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008;14:238–49.

    CAS  PubMed  Google Scholar 

  79. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458:776–9.

  80. Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, et al. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med. 2011;208:2163–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Reavie L, Buckley SM, Loizou E, Takeishi S, Aranda-Orgilles B, Ndiaye-Lobry D, et al. Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell. 2013;23:362–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Abraham SA, Hopcroft LE, Carrick E, Drotar ME, Dunn K, Williamson AJ, et al. Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature. 2016;534:341–6.

    PubMed  PubMed Central  Google Scholar 

  83. Lai D, Chen M, Su J, Liu X, Rothe K, Hu K, et al. PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL(+) human leukemia. Sci Transl Med. 2018;10:eaan8735.

  84. Li L, Wang L, Li L, Wang Z, Ho Y, McDonald T, et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell. 2012;21:266–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Jin Y, Zhou J, Xu F, Jin B, Cui L, Wang Y, et al. Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia. The. J Clin Investig. 2016;126:3961–80.

    PubMed  Google Scholar 

  86. Cramer-Morales K, Nieborowska-Skorska M, Scheibner K, Padget M, Irvine DA, Sliwinski T, et al. Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. Blood. 2013;122:1293–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ma L, Pak ML, Ou J, Yu J, St Louis P, Shan Y, et al. Prosurvival kinase PIM2 is a therapeutic target for eradication of chronic myeloid leukemia stem cells. Proc Natl Acad Sci USA. 2019;116:10482–7.

    CAS  PubMed  Google Scholar 

  88. Goff DJ, Court Recart A, Sadarangani A, Chun HJ, Barrett CL, Krajewska M, et al. A Pan-BCL2 inhibitor renders bone-marrow-resident human leukemia stem cells sensitive to tyrosine kinase inhibition. Cell Stem Cell. 2013;12:316–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Prost S, Relouzat F, Spentchian M, Ouzegdouh Y, Saliba J, Massonnet G, et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPARgamma agonists. Nature. 2015;525:380–3.

    CAS  PubMed  Google Scholar 

  90. Bellodi C, Lidonnici MR, Hamilton A, Helgason GV, Soliera AR, Ronchetti M, et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Investig. 2009;119:1109–23.

    CAS  PubMed  Google Scholar 

  91. Baquero P, Dawson A, Mukhopadhyay A, Kuntz EM, Mitchell R, Olivares O, et al. Targeting quiescent leukemic stem cells using second generation autophagy inhibitors. Leukemia. 2019;33:981–94.

    CAS  PubMed  Google Scholar 

  92. Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 2008;453:1072–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Ye D, Wolff N, Li L, Zhang S, Ilaria RL Jr. STAT5 signaling is required for the efficient induction and maintenance of CML in mice. Blood. 2006;107:4917–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Gallipoli P, Cook A, Rhodes S, Hopcroft L, Wheadon H, Whetton AD, et al. JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood. 2014;124:1492–501.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Eiring AM, Kraft IL, Page BD, O’Hare T, Gunning PT, Deininger MW. STAT3 as a mediator of BCR-ABL1-independent resistance in chronic myeloid leukemia. Leuk Suppl 2014;3:S5–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kuntz EM, Baquero P, Michie AM, Dunn K, Tardito S, Holyoake TL, et al. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat Med. 2017;23:1234–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463:676–80.

    CAS  PubMed  Google Scholar 

  98. Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature. 2010;466:765–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Jiang Q, Crews LA, Barrett CL, Chun HJ, Court AC, Isquith JM, et al. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2013;110:1041–6.

    CAS  PubMed  Google Scholar 

  100. Scott MT, Korfi K, Saffrey P, Hopcroft LE, Kinstrie R, Pellicano F, et al. Epigenetic reprogramming sensitizes CML stem cells to combined EZH2 and tyrosine kinase inhibition. Cancer Discov. 2016;6:1248–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Xie H, Peng C, Huang J, Li BE, Kim W, Smith EC, et al. Chronic myelogenous leukemia-Initiating Cells Require Polycomb Group Protein EZH2. Cancer Discov. 2016;6:1237–47.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Cancer Institute (NIH) grant NIH grants 1 R01 CA257602-01 and R01CA178397-05 (MWD), and P30CA042014.

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Authors and Affiliations

  1. Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA

    Helong Zhao & Michael W. Deininger

  2. Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA

    Michael W. Deininger

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  1. Helong Zhao
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Correspondence to Michael W. Deininger.

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MWD is an advisory board member of Blueprint, Takeda, Incyte, and Sangamo, is a consultant for Blueprint, Fusion Pharma, Medscape, Novartis, Sangamo and DisperSol, and receives research funding from Blueprint, Takeda, Novartis, Incyte, SPARC, Leukemia & Lymphoma Society, and Pfizer.

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Zhao, H., Deininger, M.W. Declaration of Bcr-Abl1 independence. Leukemia 34, 2827–2836 (2020). https://doi.org/10.1038/s41375-020-01037-9

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