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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.
The authors identify pre-leukaemic haematopoietic stem cells (HSCs) in patients with acute myeloid leukaemia; these pre-leukaemic HSCs have the capacity of normal multi-lineage haematopoietic differentiation with a competitive growth advantage over wild-type HSCs, and owing to their persistence may serve as a reservoir for therapeutic resistance and relapse.
Pre-cancer processes in leukaemia
It is thought that almost all cancers are clonal — the progeny of a single mutated cell — but the evolutionary pathways that lead from a first mutation to the many different forms of cancer remain largely unknown. John Dick and colleagues examined peripheral blood and bone marrow samples from patients with acute myeloid leukaemia (AML) and identified leukaemic blasts with both
DNMT3A
mut
and
NPM1c
mutations in a large proportion of patients. Also present were pre-leukaemic haematopoietic stem cells (HSCs) that carried
DNMT3A
mut
without
NPM1c
. These cells retained the ability to generate different cell types and thereby sustain normal haematopoiesis but have a competitive repopulation advantage over wild-type HSCs and can persist after remission following chemotherapy, so may act as a reservoir for the accumulation of further mutations and therapeutic resistance. This work points to mutations in
DNMT3A
and other genes that give rise to pre-leukaemic HSCs as possible drug targets and suggests that the identification and treatment of pre-leukaemic clones may help combat therapeutic resistance.