1. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia
- Author
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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 D. McPherson, Thomas J. Hudson, The HALT Pan-Leukemia Gene Panel Consortium, Andrew M. K. Brown, Fouad Yousif, Quang M. Trinh, Lincoln D. Stein, Mark D. Minden, Jean C. Y. Wang, and John E. Dick
- Subjects
Myeloid ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,T-Lymphocytes ,Cellular differentiation ,Drug Resistance ,HALT Pan-Leukemia Gene Panel Consortium ,DNA Methyltransferase 3A ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,2.1 Biological and endogenous factors ,DNA (Cytosine-5-)-Methyltransferases ,Aetiology ,Cancer ,Pediatric ,0303 health sciences ,Leukemia ,Multidisciplinary ,Remission Induction ,Nuclear Proteins ,Cell Differentiation ,Hematology ,Isocitrate Dehydrogenase ,3. Good health ,Leukemia, Myeloid, Acute ,Haematopoiesis ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Heterografts ,Female ,Stem Cell Research - Nonembryonic - Non-Human ,Stem cell ,Nucleophosmin ,Cell Division ,NPM1 ,Childhood Leukemia ,Pediatric Cancer ,General Science & Technology ,Acute ,Biology ,SCID ,Article ,03 medical and health sciences ,Rare Diseases ,Cancer stem cell ,Genetics ,medicine ,Animals ,Humans ,Cell Lineage ,030304 developmental biology ,Progenitor ,Hematopoietic Stem Cells ,Stem Cell Research ,medicine.disease ,Clone Cells ,Hematopoiesis ,Mutation ,Immunology ,Inbred NOD ,Neoplasm ,Neoplasm Transplantation - Abstract
Item does not contain fulltext 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.
- Published
- 2014
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