Molecular biology and cytogenetics of chronic myeloid leukemia

Marina Konopleva, Alfonso Quintás Cardama, Hagop Kantarjian, Jorge Cortes

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Scopus citations


Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the t(9;22)(q34;q11) balanced reciprocal translocation that causes the fusion of a portion of chromosome 9 to chromosome 22 (der22), thereby replacing a fragment of chromosome 22 which fuses to chromosome 9 (der9). The resultant minute chromosome der22, designated as the Philadelphia chromosome (Ph), is the hallmark of CML (Quintas-Cardama and Cortes, Blood 113(8):1619-30, 2009). The molecular event resulting from this translocation is the hybrid BCR-ABL1 oncogene, which encodes the constitutively active BCR-ABL1 protein kinase (Quintas-Cardama and Cortes, Blood 113(8):1619-30, 2009). The BCR-ABL1 protein can transform cells through phosphorylation of tyrosine residues on a variety of intermediary proteins that transmit signals from the cytoplasm to the nucleus. The ultimate proof that BCR-ABL1 kinase expression can induce CML was furnished by experiments in which murine bone marrow was transfected with a retrovirus encoding BCR-ABL1 and transplanted into irradiated syngeneic recipients. Transplanted recipients developed any of several hematologic malignancies, most frequently a myeloproliferative syndrome that resembles chronic-phase CML (Daley et al., Science 247(4944):824-30, 1990). The demonstration in animal models that BCR-ABL1 kinase activity was a causal event that recapitulated the development of CML cellular transformation provided the rationale for developing molecules that selectively inhibited the BCR-ABL1 kinase activity. Kinase-based assays demonstrated that imatinib, the first tyrosine kinase inhibitor (TKI) developed for the treatment of CML, potently inhibited ABL1 kinase (Buchdunger et al., Cancer Res 56(1):100-4, 1996; Druker et al., Nat Med 2(5):561-6, 1996) and that this inhibitory activity translated into impressive clinical activity (O’brien et al., N Engl J Med 348(11):994-1004, 2003). The remarkable clinical success of imatinib propelled the rational design and development of other TKIs (e.g., nilotinib, dasatinib, bosutinib, ponatinib) aided by structural biology and high-throughput medicinal chemistry methods. Despite these agents’ clinical activity, patients receiving TKI therapy frequently continue to have measurable amounts of residual disease and in some the TKI therapy eventually fails. Among patients with accelerated phase (AP) or blastic phase (BP) CML, responses are less frequent and often short-lived (Druker et al., N Engl J Med 344(14):1038-42, 2001). These shortcomings of TKI therapy have spurred efforts to understand the behavior of CML stem cells, and the mechanisms of resistance to TKIs and the molecular basis of transformation to AP and BP.

Original languageEnglish (US)
Title of host publicationNeoplastic Diseases of the Blood
PublisherSpringer International Publishing
Number of pages19
ISBN (Electronic)9783319642635
ISBN (Print)9783319642628
StatePublished - Jan 1 2018
Externally publishedYes


  • BCR-ABL1
  • Chronic myeloid leukemia
  • Imatinib
  • Mutations
  • Quiescence
  • Resistance
  • Stem cells
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Medicine(all)


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