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Leukemia. 2016 Apr;30(4):906-13. doi: 10.1038/leu.2015.337. Epub 2015 Dec 9.

Age-related mutations and chronic myelomonocytic leukemia.

Author information

1
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
2
Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
3
Department of Pathology, University of Utah, Salt Lake City, UT, USA.
4
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
5
North American Association of Central Cancer Registries, Springfield, IL, USA.
6
Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
7
Division of Hematology, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA, USA.
8
Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.

Abstract

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

PMID:
26648538
PMCID:
PMC5096889
DOI:
10.1038/leu.2015.337
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

CCM and MWD report a potential related conflict of interest of research funding from Agilent Technologies, Inc. MWD also reports a potential related conflict of interest of research funding from Celgene, Inc. All other authors declare no conflict of interests.

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