title: Age-related mutations and chronic myelomonocytic leukemia.
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.
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.|Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Mason
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Khorashad
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Tantravahi
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Kelley
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Zabriskie
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yan
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Pomicter
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Reynolds
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Eiring
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Kronenberg
authors.affiliation: North American Association of Central Cancer Registries, Springfield, IL, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Sherman
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Dalley
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors.forename: K-H
authors.initials: KH
authors.lastname: Dao
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yandell
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Division of Hematology, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gotlib
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.|Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: T
authors.initials: T
authors.lastname: O'Hare
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.|Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D005500:Follow-Up Studies; D006410:Hematopoiesis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011506:Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D011506:Proteins; D016601:RNA-Binding Proteins; C000590560:ZBTB8OS protein, human