Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia

Nature. 2014 Feb 20;506(7488):328-33. doi: 10.1038/nature13038. Epub 2014 Feb 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Division
  • Cell Lineage
  • Clone Cells / cytology
  • Clone Cells / metabolism
  • Clone Cells / pathology
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Hematopoiesis
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Heterografts
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Leukemia, Myeloid, Acute / diagnosis
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation / genetics
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / cytology*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Nuclear Proteins / genetics
  • Remission Induction
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology

Substances

  • Nuclear Proteins
  • nucleophosmin
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A