Journal Article

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia

McPherson, John D., Medeiros, Jessie J. F., Hudson, Thomas J., Brown, Andrew M. K., Kim, Hyeoung Joon, Mitchell, Amanda, Doedens, Monica, Yousif, Fouad, Shlush, Liran I., Minden, Mark D., Schimmer, Aaron D., Wang, Jean C. Y., Schuh, Andre C., Gupta, Vikas, Zandi, Sasan, Marke, Rene, Trinh, Quang M., Dick, John E., Kennedy, James A., McLeod, Jessica L., Lee, Kwon, Chen, Weihsu Claire, Brandwein, Joseph M., Yee, Karen W., Pan-Leukemia Gene Panel Consortium, The HALT, Stein, Lincoln D.

2014

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 45 / 45/100 / 45/23 / 631/67/2329 / 631/67/68 / 631/67/71 / Acute leukemia / Animals / Cell Differentiation / Cell Division / Cell Lineage / Clone Cells - cytology / Clone Cells - metabolism / Clone Cells - pathology / Diagnosis / DNA (Cytosine-5-)-Methyltransferases - genetics / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA Methyltransferase 3A / Drug Resistance, Neoplasm - drug effects / Female / Genetic aspects / Health aspects / Hematopoiesis / Hematopoietic stem cells / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - drug effects / Hematopoietic Stem Cells - metabolism / Hematopoietic Stem Cells - pathology / Heterografts / Humanities and Social Sciences / Humans / Identification and classification / Isocitrate Dehydrogenase - genetics / Leukemia / Leukemia, Myeloid, Acute - diagnosis / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Mice / Mice, Inbred NOD / Mice, SCID / multidisciplinary / Mutation - genetics / Neoplasm Transplantation / Neoplastic Stem Cells - cytology / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Nuclear Proteins - genetics / Nucleophosmin / Physiological aspects / Remission Induction / Science / Stem cells / T-Lymphocytes - metabolism / T-Lymphocytes - pathology