Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia

Liran I. Shlush, Sasan Zandi, Amanda Mitchell, Weihsu Claire Chen, Joseph M. Brandwein, Vikas Gupta, James A. Kennedy, Aaron D. Schimmer, Andre C. Schuh, Karen W. Yee, Jessica L. McLeod, Monica Doedens, Jessie J F Medeiros, Rene Marke, Hyeoung Joon Kim, Kwon Lee, John Douglas Mcpherson, Thomas J. Hudson, Andrew M K Brown, Quang M. TrinhLincoln D. Stein, Mark D. Minden, Jean C Y Wang, John E. Dick

Research output: Contribution to journalArticle

794 Scopus citations

Abstract

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A mut) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A mut-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A mut arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.

Original languageEnglish (US)
Pages (from-to)328-333
Number of pages6
JournalNature
Volume506
Issue number7488
DOIs
StatePublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)
  • General

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    Shlush, L. I., Zandi, S., Mitchell, A., Chen, W. C., Brandwein, J. M., Gupta, V., Kennedy, J. A., Schimmer, A. D., Schuh, A. C., Yee, K. W., McLeod, J. L., Doedens, M., Medeiros, J. J. F., Marke, R., Kim, H. J., Lee, K., Mcpherson, J. D., Hudson, T. J., Brown, A. M. K., ... Dick, J. E. (2014). Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature, 506(7488), 328-333. https://doi.org/10.1038/nature13038