Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Molecular genetics of chronic myeloid leukemia

Richard A Van Etten, MD, PhD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD


Chronic myeloid leukemia (CML, also known as chronic myelocytic, myelogenous, or granulocytic leukemia) is classified as one of the myeloproliferative neoplasms, along with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). (See "Overview of the myeloproliferative neoplasms".)

This group of diseases shares several distinct features:

They are clonal disorders of hematopoiesis that arise in a hematopoietic stem or early progenitor cell.

They are characterized by the dysregulated production of a particular lineage of mature myeloid cells with fairly normal differentiation.

They exhibit a variable tendency to progress to acute leukemia.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Sep 29, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Verfaillie CM. Biology of chronic myelogenous leukemia. Hematol Oncol Clin North Am 1998; 12:1.
  2. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med 1999; 341:164.
  3. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960; 132:1197.
  4. Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243:290.
  5. Maniatis AK, Amsel S, Mitus WJ, Coleman N. Chromosome pattern of bone marrow fibroblasts in patients with chronic granulocytic leukaemia. Nature 1969; 222:1278.
  6. de Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1982; 300:765.
  7. Heisterkamp N, Stephenson JR, Groffen J, et al. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature 1983; 306:239.
  8. Goff SP, Gilboa E, Witte ON, Baltimore D. Structure of the Abelson murine leukemia virus genome and the homologous cellular gene: studies with cloned viral DNA. Cell 1980; 22:777.
  9. Abelson HT, Rabstein LS. Lymphosarcoma: virus-induced thymic-independent disease in mice. Cancer Res 1970; 30:2213.
  10. Groffen J, Stephenson JR, Heisterkamp N, et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984; 36:93.
  11. Ben-Neriah Y, Daley GQ, Mes-Masson AM, et al. The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science 1986; 233:212.
  12. Clark SS, McLaughlin J, Timmons M, et al. Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL). Science 1988; 239:775.
  13. Fainstein E, Marcelle C, Rosner A, et al. A new fused transcript in Philadelphia chromosome positive acute lymphocytic leukaemia. Nature 1987; 330:386.
  14. Westbrook CA, Hooberman AL, Spino C, et al. Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762). Blood 1992; 80:2983.
  15. Pane F, Frigeri F, Sindona M, et al. Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction). Blood 1996; 88:2410.
  16. Melo JV. The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood 1996; 88:2375.
  17. Melo JV, Gordon DE, Cross NC, Goldman JM. The ABL-BCR fusion gene is expressed in chronic myeloid leukemia. Blood 1993; 81:158.
  18. de la Fuente J, Merx K, Steer EJ, et al. ABL-BCR expression does not correlate with deletions on the derivative chromosome 9 or survival in chronic myeloid leukemia. Blood 2001; 98:2879.
  19. Huntly BJ, Bench A, Green AR. Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia. Blood 2003; 102:1160.
  20. Huntly BJ, Guilhot F, Reid AG, et al. Imatinib improves but may not fully reverse the poor prognosis of patients with CML with derivative chromosome 9 deletions. Blood 2003; 102:2205.
  21. Kreil S, Pfirrmann M, Haferlach C, et al. Heterogeneous prognostic impact of derivative chromosome 9 deletions in chronic myelogenous leukemia. Blood 2007; 110:1283.
  22. Castagnetti F, Testoni N, Luatti S, et al. Deletions of the derivative chromosome 9 do not influence the response and the outcome of chronic myeloid leukemia in early chronic phase treated with imatinib mesylate: GIMEMA CML Working Party analysis. J Clin Oncol 2010; 28:2748.
  23. Le Gouill S, Talmant P, Milpied N, et al. Fluorescence in situ hybridization on peripheral-blood specimens is a reliable method to evaluate cytogenetic response in chronic myeloid leukemia. J Clin Oncol 2000; 18:1533.
  24. Dewald GW, Wyatt WA, Juneau AL, et al. Highly sensitive fluorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia. Blood 1998; 91:3357.
  25. Sinclair PB, Nacheva EP, Leversha M, et al. Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukemia. Blood 2000; 95:738.
  26. Herens C, Tassin F, Lemaire V, et al. Deletion of the 5'-ABL region: a recurrent anomaly detected by fluorescence in situ hybridization in about 10% of Philadelphia-positive chronic myeloid leukaemia patients. Br J Haematol 2000; 110:214.
  27. Huntly BJ, Reid AG, Bench AJ, et al. Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia. Blood 2001; 98:1732.
  28. Kolomietz E, Al-Maghrabi J, Brennan S, et al. Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis. Blood 2001; 97:3581.
  29. Hughes TP, Ambrosetti A, Barbu V, et al. Clinical value of PCR in diagnosis and follow-up of leukaemia and lymphoma: report of the third Workshop of the Molecular Biology/BMT study group. Leukemia 1991; 5:448.
  30. Goldman JM, Kaeda JS, Cross NC, et al. Clinical decision making in chronic myeloid leukemia based on polymerase chain reaction analysis of minimal residual disease. Blood 1999; 94:1484.
  31. Mensink E, van de Locht A, Schattenberg A, et al. Quantitation of minimal residual disease in Philadelphia chromosome positive chronic myeloid leukaemia patients using real-time quantitative RT-PCR. Br J Haematol 1998; 102:768.
  32. Branford S, Hughes TP, Rudzki Z. Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol 1999; 107:587.
  33. Wang L, Pearson K, Pillitteri L, et al. Serial monitoring of BCR-ABL by peripheral blood real-time polymerase chain reaction predicts the marrow cytogenetic response to imatinib mesylate in chronic myeloid leukaemia. Br J Haematol 2002; 118:771.
  34. Cross NC, White HE, Colomer D, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia 2015; 29:999.
  35. Branford S, Fletcher L, Cross NC, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008; 112:3330.
  36. Branford S, Yeung DT, Parker WT, et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014; 124:511.
  37. Hanfstein B, Shlyakhto V, Lauseker M, et al. Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia 2014; 28:1988.
  38. van Rhee F, Hochhaus A, Lin F, et al. p190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias. Blood 1996; 87:5213.
  39. Jennings LJ, George D, Czech J, et al. Detection and quantification of BCR-ABL1 fusion transcripts by droplet digital PCR. J Mol Diagn 2014; 16:174.
  40. Ponzetto C, Guerrasio A, Rosso C, et al. ABL proteins in Philadelphia-positive acute leukaemias and chronic myelogenous leukaemia blast crises. Br J Haematol 1990; 76:39.
  41. Selleri L, von Lindern M, Hermans A, et al. Chronic myeloid leukemia may be associated with several bcr-abl transcripts including the acute lymphoid leukemia-type 7 kb transcript. Blood 1990; 75:1146.
  42. Ravandi F, Cortes J, Albitar M, et al. Chronic myelogenous leukaemia with p185(BCR/ABL) expression: characteristics and clinical significance. Br J Haematol 1999; 107:581.
  43. Melo JV, Myint H, Galton DA, Goldman JM. P190BCR-ABL chronic myeloid leukaemia: the missing link with chronic myelomonocytic leukaemia? Leukemia 1994; 8:208.
  44. Verma D, Kantarjian HM, Jones D, et al. Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood 2009; 114:2232.
  45. Mittre H, Leymarie P, Macro M, Leporrier M. A new case of chronic myeloid leukemia with c3/a2 BCR/ABL junction. Is it really a distinct disease? Blood 1997; 89:4239.
  46. Mills KI, MacKenzie ED, Birnie GD. The site of the breakpoint within the bcr is a prognostic factor in Philadelphia-positive CML patients. Blood 1988; 72:1237.
  47. Shtalrid M, Talpaz M, Kurzrock R, et al. Analysis of breakpoints within the bcr gene and their correlation with the clinical course of Philadelphia-positive chronic myelogenous leukemia. Blood 1988; 72:485.
  48. Castor A, Nilsson L, Astrand-Grundström I, et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 2005; 11:630.
  49. Schenk TM, Keyhani A, Bottcher S, et al. Multilineage involvement of Philadelphia chromosome positive acute lymphoblastic leukemia. Leukemia 1998; 12:666.
  50. Cobaleda C, Gutiérrez-Cianca N, Pérez-Losada J, et al. A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. Blood 2000; 95:1007.
  51. Savage DG, Szydlo RM, Goldman JM. Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. Br J Haematol 1997; 96:111.
  52. Gorusu M, Benn P, Li Z, Fang M. On the genesis and prognosis of variant translocations in chronic myeloid leukemia. Cancer Genet Cytogenet 2007; 173:97.
  53. Huret JL. Complex translocations, simple variant translocations and Ph-negative cases in chronic myelogenous leukaemia. Hum Genet 1990; 85:565.
  54. Richebourg S, Eclache V, Perot C, et al. Mechanisms of genesis of variant translocation in chronic myeloid leukemia are not correlated with ABL1 or BCR deletion status or response to imatinib therapy. Cancer Genet Cytogenet 2008; 182:95.
  55. El-Zimaity MM, Kantarjian H, Talpaz M, et al. Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome. Br J Haematol 2004; 125:187.
  56. Marzocchi G, Castagnetti F, Luatti S, et al. Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis. Blood 2011; 117:6793.
  57. Kurzrock R, Kantarjian HM, Shtalrid M, et al. Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course. Blood 1990; 75:445.
  58. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 2013; 368:1781.