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Clonal chromosomal abnormalities in CD34+/CD38− hematopoietic cells from cytogenetically normal chronic myeloid leukemia patients with a complete cytogenetic response to tyrosine kinase inhibitors

Leukemia volume 24, pages 1525–1528 (2010)Cite this article

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Clonal chromosomal abnormalities in Philadelphia-negative cells (CCA/Ph–) have been identified in 3–15% of chronic myeloid leukemia (CML) patients with a partial or complete cytogenetic response (CCyR) to imatinib.1 Trisomy 8 and deletions of chromosome 7 (either monosomy 7 or del 7(q)) account for the majority of cases, although a range of other karyotypic changes were seen at lower frequency. A recent study reported CCA/Ph− in patients on dasatinib, indicating that the phenomenon is not limited to imatinib therapy. In some patients, CCA/Ph− is associated with a myelodysplastic syndrome, and progression to acute myeloid leukemia has been reported.1, 2 A single-center report suggested inferior survival in newly diagnosed patients who develop CCA/Ph–.3 However, a larger study found that CCA/Ph– does not adversely affect the prognosis of patients with a major cytogenetic response to imatinib, indicating that this is a mostly benign condition.4 The reported incidence of CCA/Ph– is based on metaphase karyotyping, which is limited by the small number of cells analyzed and by the fact that only cells are assayed that can be induced to divide within the culture period. We thus hypothesized that conventional karyotyoping may underestimate the incidence of CCA/Ph– and decided to screen CD34+/CD38− cells from a cohort of CML patients with a CCyR to tyrosine kinase inhibitor (TKI) therapy for abnormalities of chromosomes 7 and 8. This primitive cell compartment is known to be enriched for hematopoietic progenitor and stem cells.5 We find CCA/Ph– in CD34+/CD38− cells from 4 of 19 patients, suggesting that CCA/Ph– is more common than previously appreciated.

Samples were from consecutive CML patients on TKI therapy who were undergoing bone marrow aspirates at the Oregon Health & Science University as part of their clinical care. The only selection criterion was a normal karyotype on the previous biopsy. At the start of TKI therapy, one patient (number 14) was in the accelerated phase, whereas all others were in the chronic phase. All patients provided informed consent to an institutional review board-approved protocol. Control samples (normal bone marrow mononuclear cells) were purchased from a commercial supplier.

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Acknowledgements

We thank Jonathan VanDycke for help with FACS analysis. This work was supported in part by the NHLBI Grant HL082978-01 (MD), the Leukemia and Lymphoma Society 7393–06: Specialized Center of Research (MD). Michael Deininger is a Scholar in Clinical Research of the Leukemia & Lymphoma Society.

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Author notes

  1. T Bumm, J Deininger and A H Newell: These authors contributed equally to this work.

Authors and Affiliations

  1. Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA

    T Bumm, J Deininger, M Mauro, B Druker & M Deininger

  2. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA

    A H Newell, H Lawce & S Olson

  3. Howard Hughes Medical Institute, USA

    B Druker

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  1. T Bumm
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  2. J Deininger
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Correspondence to J Deininger.

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Competing interests

Oregon Health & Science University and BD have a financial interest in MolecularMD. The technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the Oregon Health & Science University Conflict of Interest in Research Committee and the Integrity Program Oversight Council. Oregon Health & Science University has clinical trial contracts with Novartis and Bristol-Myers Squibb to pay for patient costs, nurse and data manager salaries, and institutional overhead. BD does not derive salary nor does his laboratory receive funds from these contracts. MD is a consultant for Novartis and Bristol-Myers Squibb and was supported by Genzyme and Cytopia. The remaining authors declare no competing financial interests.

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Bumm, T., Deininger, J., Newell, A. et al. Clonal chromosomal abnormalities in CD34+/CD38− hematopoietic cells from cytogenetically normal chronic myeloid leukemia patients with a complete cytogenetic response to tyrosine kinase inhibitors. Leukemia 24, 1525–1528 (2010). https://doi.org/10.1038/leu.2010.123

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