Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia

D. W. Sherbenou, O. Hantschel, L. Turaga, I. Kaupe, S. Willis, T. Bumm, Richard Press, G. Superti-Furga, Brian Druker, M. W. Deininger

Research output: Contribution to journalArticle

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Abstract

The BCR-ABL oncogenic tyrosine kinase causes chronic myeloid leukemia and is the target for imatinib therapy. During imatinib treatment, cells are selected in some patients with BCR-ABL kinase domain mutations that render decreased drug sensitivity. In addition, some patients express deletion mutants of BCR-ABL, apparently due to missplicing. Most commonly these deletion mutants lack a significant portion of the kinase domain that includes the P-loop. We describe a screen for such mutations in patients with CML and demonstrate that they are not oncogenic and are catalytically inactive. We hypothesized that coexpressing BCR-ABL deletion mutants has a dominant-negative effect on the native form through heterocomplex formation. However, upon coexpression of native and deletion mutant BCR-ABL in Ba/F3 cells, growth factor independence is maintained and signaling is activated normally. Despite this, these cells have increased imatinib sensitivity compared to cells expressing only native BCR-ABL. Thus, it will be important to investigate the prognostic impact of coexpression of deletion mutants in CML patients during imatinib treatment.

Original languageEnglish (US)
Pages (from-to)1184-1190
Number of pages7
JournalLeukemia
Volume22
Issue number6
DOIs
StatePublished - Jun 2008

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Mutation
Protein-Tyrosine Kinases
Intercellular Signaling Peptides and Proteins
Therapeutics
Imatinib Mesylate
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Sherbenou, D. W., Hantschel, O., Turaga, L., Kaupe, I., Willis, S., Bumm, T., ... Deininger, M. W. (2008). Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia. Leukemia, 22(6), 1184-1190. https://doi.org/10.1038/leu.2008.65

Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia. / Sherbenou, D. W.; Hantschel, O.; Turaga, L.; Kaupe, I.; Willis, S.; Bumm, T.; Press, Richard; Superti-Furga, G.; Druker, Brian; Deininger, M. W.

In: Leukemia, Vol. 22, No. 6, 06.2008, p. 1184-1190.

Research output: Contribution to journalArticle

Sherbenou, DW, Hantschel, O, Turaga, L, Kaupe, I, Willis, S, Bumm, T, Press, R, Superti-Furga, G, Druker, B & Deininger, MW 2008, 'Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia', Leukemia, vol. 22, no. 6, pp. 1184-1190. https://doi.org/10.1038/leu.2008.65
Sherbenou DW, Hantschel O, Turaga L, Kaupe I, Willis S, Bumm T et al. Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia. Leukemia. 2008 Jun;22(6):1184-1190. https://doi.org/10.1038/leu.2008.65
Sherbenou, D. W. ; Hantschel, O. ; Turaga, L. ; Kaupe, I. ; Willis, S. ; Bumm, T. ; Press, Richard ; Superti-Furga, G. ; Druker, Brian ; Deininger, M. W. / Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia. In: Leukemia. 2008 ; Vol. 22, No. 6. pp. 1184-1190.
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