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Acute Leukemias

Heterogeneity of clonal expansion and maturation-linked mutation acquisition in hematopoietic progenitors in human acute myeloid leukemia

Leukemia volume 28, pages 1969–1977 (2014)Cite this article

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Abstract

Recent technological advances led to an appreciation of the genetic complexity of human acute myeloid leukemia (AML), but underlying progenitor cells remain poorly understood because their rarity precludes direct study. We developed a co-culture method integrating hypoxia, aryl hydrocarbon receptor inhibition and micro-environmental support via human endothelial cells to isolate these cells. X-chromosome inactivation studies of the least mature precursors derived following prolonged culture of CD34+/CD33− cells revealed polyclonal growth in highly curable AMLs, suggesting that mutations necessary for clonal expansion were acquired in more mature progenitors. Consistently, in core-binding factor (CBF) leukemias with known complementing mutations, immature precursors derived following prolonged culture of CD34+/CD33− cells harbored neither mutation or the CBF mutation alone, whereas more mature precursors often carried both mutations. These results were in contrast to those with leukemias with poor prognosis that showed clonal dominance in the least mature precursors. These data indicate heterogeneity among progenitors in human AML that may have prognostic and therapeutic implications.

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Acknowledgements

Research reported in this publication was supported by grants from the National Cancer Institute/National Institutes of Health (P30-CA015704-35S6 (to RBW), U10-CA098453 (NIH COG Chair Grant, Children’s Hospital of Philadelphia), and U10-CA32102 and U10-CA38926 (to SWOG)), Alex’s Lemonade Stand Foundation (to RBW), the Hope Foundation (to RBW), the Ronald McDonald House Charities of Southern California and Couples Against Leukemia (to RBW), the Leukemia & Lymphoma Society (Specialized Center for Research (SCOR) grant #7008-08 to IDB), a St. Baldrick's Foundation Career Development Award (to JAP) and a CureSearch Research Fellowship Award (to JAP).

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Author notes

  1. J M Lionberger

    Present address: 8Current address: Division of Hematology and Medical Oncology, Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA,

Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    R B Walter, G S Laszlo, J M Lionberger, J A Pollard, K H Harrington, C J Gudgeon, S Meshinchi, F R Appelbaum & I D Bernstein

  2. Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA

    R B Walter

  3. Department of Epidemiology, University of Washington, Seattle, WA, USA

    R B Walter

  4. Department of Pediatrics, University of Washington, Seattle, WA, USA

    J A Pollard, S Meshinchi & I D Bernstein

  5. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    M Othus

  6. Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA

    S Rafii

  7. Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA

    F R Appelbaum

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  1. R B Walter
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Correspondence to R B Walter.

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Presented in part at the 52nd and 55th Annual Meetings of the American Society of Hematology (4–7 December 2010, Orlando, FL, USA; and 7–10 December 2013, New Orleans, LA, USA).

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Walter, R., Laszlo, G., Lionberger, J. et al. Heterogeneity of clonal expansion and maturation-linked mutation acquisition in hematopoietic progenitors in human acute myeloid leukemia. Leukemia 28, 1969–1977 (2014). https://doi.org/10.1038/leu.2014.107

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