Molecular biology and cytogenetics of chronic myeloid leukemia

Alfonso Quintás Cardama, Hagop Kantarjian, Jorge Cortes

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

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 [1]. The molecular event resulting from this translocation is the hybrid BCR-ABL1 oncogene, which encodes the constitutively active BCR-ABL1 protein kinase [1]. The BCR-ABL1 protein can transform cells through phosphorylation of tyrosine residues on a variety of intermediary proteins that transmits 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 several hematologic malignancies, most frequently a myeloproliferative syndrome that resembles very closely the chronic phase of CML [2]. The demonstration that the BCR-ABL1 kinase activity played a crucial role in cellular transformation provided the rationale for developing molecules aimed at targeting such activity. Kinase-based assays demonstrated that imatinib, the first tyrosine kinase inhibitor (TKI) developed for the treatment of CML, inhibited potently ABL1 kinase [3, 4], and more importantly, this inhibitory activity translated into impressive clinical activity [5]. The remarkable clinical success of imatinib propelled the rational design and development of other TKIs (e.g. nilotinib, dasatinib, bosutinib) aided by structural biology and high throughput medicinal chemistry methods. In spite of their clinical activity, patients receiving TKI therapy frequently harbor measurable amounts of residual disease, some may eventually fail TKI therapy, and in those with accelerated (AP) or blastic phase (BP) CML, responses are rare and, when they occur, typically short-lived [6]. These shortcomings of TKI therapy have spurred research efforts aimed at understanding the behavior of CML stem cells, the molecular basis of transformation to AP and BP, and the mechanisms of resistance to TKIs.

Original languageEnglish (US)
Title of host publicationNeoplastic Diseases of the Blood
PublisherSpringer New York
Pages29-44
Number of pages16
ISBN (Electronic)9781461437642
ISBN (Print)1461437636, 9781461437635
DOIs
StatePublished - Nov 1 2013
Externally publishedYes

Fingerprint

Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cytogenetics
Molecular Biology
Protein-Tyrosine Kinases
Phosphotransferases
Leukemia, Myeloid, Chronic Phase
Chromosomes, Human, Pair 22
Chromosomes, Human, Pair 9
Myeloid Progenitor Cells
Philadelphia Chromosome
Pharmaceutical Chemistry
Hematologic Neoplasms
Retroviridae
Therapeutics
Oncogenes
Protein Kinases
Tyrosine
Cytoplasm
Proteins
Chromosomes

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cardama, A. Q., Kantarjian, H., & Cortes, J. (2013). Molecular biology and cytogenetics of chronic myeloid leukemia. In Neoplastic Diseases of the Blood (pp. 29-44). Springer New York. https://doi.org/10.1007/978-1-4614-3764-2_4

Molecular biology and cytogenetics of chronic myeloid leukemia. / Cardama, Alfonso Quintás; Kantarjian, Hagop; Cortes, Jorge.

Neoplastic Diseases of the Blood. Springer New York, 2013. p. 29-44.

Research output: Chapter in Book/Report/Conference proceedingChapter

Cardama, AQ, Kantarjian, H & Cortes, J 2013, Molecular biology and cytogenetics of chronic myeloid leukemia. in Neoplastic Diseases of the Blood. Springer New York, pp. 29-44. https://doi.org/10.1007/978-1-4614-3764-2_4
Cardama AQ, Kantarjian H, Cortes J. Molecular biology and cytogenetics of chronic myeloid leukemia. In Neoplastic Diseases of the Blood. Springer New York. 2013. p. 29-44 https://doi.org/10.1007/978-1-4614-3764-2_4
Cardama, Alfonso Quintás ; Kantarjian, Hagop ; Cortes, Jorge. / Molecular biology and cytogenetics of chronic myeloid leukemia. Neoplastic Diseases of the Blood. Springer New York, 2013. pp. 29-44
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