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Stem Cells

The role of minor subpopulations within the leukemic blast compartment of AML patients at initial diagnosis in the development of relapse

Leukemia volume 26, pages 1313–1320 (2012)Cite this article

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Abstract

The majority of pediatric and younger adult (<60 years) AML patients achieve complete remission. However, 30–40% of patients relapse and display a dismal outcome. Recently we described a frequent instability of type I/II mutations between diagnosis and relapse. Here, we explored the hypothesis that these mutational shifts originate from clonal selection during treatment/disease progression. Subfractions of blasts from initial diagnosis samples were cell sorted and their mutational profiles were compared with those of the corresponding relapse samples of 7 CD34+ AML patients. At diagnosis, subfractions of the CD45dimCD34+CD38dim/− compartment were heterogeneous in the distribution of mutations, when compared to the whole CD45dimCD34+ blast compartment in 6 out of 7 patients. Moreover, within CD45dimCD34+CD38dim/− fraction of initial samples of 5 of these 6 AML patients, we found evidence for the presence of a minor, initially undetected subpopulation with a specific mutational profile that dominated the bulk of leukemic blasts at relapse. In conclusion, our findings lend support to the AML oligoclonality concept and provide molecular evidence for selection and expansion of a chemo-resistant subpopulation towards development of relapse. These results imply that early detection of pre-existing drug-resistant leukemic subpopulations is crucial for relapse prevention by proper timing of targeted treatment.

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Acknowledgements

This work was supported by the Dutch Cancer Society (VU 2005-3666, JC), Stichting KiKa/Children Cancer-free (GJLK), the Netherlands Organization for Scientific Research (YGA) and The Royal Netherlands Academy of Arts and Sciences (YGA). YGA is a recipient of the Royal Netherlands Academy of Arts and Sciences Award for Visiting Professors.

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Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Amsterdam, The Netherlands

    C Bachas, Z J Kwidama, G J L Kaspers & J Cloos

  2. Hematology, VU University Medical Center, Amsterdam, The Netherlands

    C Bachas, G J Schuurhuis, Z J Kwidama, A Kelder, F Wouters, A N Snel & J Cloos

  3. Department of Biology, The Fred Wyszkowski Cancer Research Laboratory, Technion-Israel Institute of Technology, Haifa, Israel

    Y G Assaraf

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Bachas, C., Schuurhuis, G., Assaraf, Y. et al. The role of minor subpopulations within the leukemic blast compartment of AML patients at initial diagnosis in the development of relapse. Leukemia 26, 1313–1320 (2012). https://doi.org/10.1038/leu.2011.383

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