Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes
Autor: | Mignon L. Loh, Jeffrey H. Davis, Rochelle Yanofsky, Tamara Lamprecht, Paul Rogers, James R. Downing, Sara J. Israels, Jason R. Schwartz, Victoria Bryant, Jeffery M. Klco, Maria del pilar Alzamora, Michael Walsh, Raul C. Ribeiro, Kevin Shannon, Stuart H. Gold, Jing Ma, Jasmine C. Wong, Charles G. Mullighan, William L. Carroll |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male medicine.medical_specialty Myeloid Somatic cell Chromosome Disorders Germline Evolution Molecular 03 medical and health sciences Internal medicine hemic and lymphatic diseases Neoplasms medicine Humans Genetic Predisposition to Disease Germ-Line Mutation Chromosome 7 (human) Hematology business.industry Tumor Suppressor Proteins Cell Cycle Intracellular Signaling Peptides and Proteins Myeloid leukemia Proteins General Medicine medicine.disease Pedigree Gene Expression Regulation Neoplastic Leukemia Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure Hematologic Neoplasms Myelodysplastic Syndromes Cancer research Disease Progression Female Bone marrow Chromosome Deletion business Chromosomes Human Pair 7 Research Article |
Zdroj: | JCI insight. 3(14) |
ISSN: | 2379-3708 |
Popis: | Germline SAMD9 and SAMD9L mutations cause a spectrum of multisystem disorders that carry a markedly increased risk of developing myeloid malignancies with somatic monosomy 7. Here, we describe 16 siblings, the majority of which were phenotypically normal, from 5 families diagnosed with myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270) who primarily had onset of hematologic abnormalities during the first decade of life. Molecular analyses uncovered germline SAMD9L (n = 4) or SAMD9 (n = 1) mutations in these families. Affected individuals had a highly variable clinical course that ranged from mild and transient dyspoietic changes in the bone marrow to a rapid progression of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with monosomy 7. Expression of these gain-of-function SAMD9 and SAMD9L mutations reduces cell cycle progression, and deep sequencing demonstrated selective pressure favoring the outgrowth of clones that have either lost the mutant allele or acquired revertant mutations. The myeloid malignancies of affected siblings acquired cooperating mutations in genes that are also altered in sporadic cases of AML characterized by monosomy 7. These data have implications for understanding how SAMD9 and SAMD9L mutations contribute to myeloid transformation and for recognizing, counseling, and treating affected families. |
Databáze: | OpenAIRE |
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