Mixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DNMT3A and activated signaling genes.

TitleMixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DNMT3A and activated signaling genes.
Publication TypeJournal Article
Year of Publication2016
AuthorsEckstein, OS, Wang, L, Punia, JN, Kornblau, SM, Andreeff, M, Wheeler, DA, Goodell, MA, Rau, RE
JournalExp Hematol
Volume44
Issue8
Pagination740-4
Date Published2016 Aug
ISSN1873-2399
KeywordsAdolescent, Adult, Clonal Evolution, Cluster Analysis, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, Epigenesis, Genetic, Exome, Gene Expression Profiling, Gene Expression Regulation, Leukemic, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Biphenotypic, Acute, Middle Aged, Mutation, Signal Transduction, Young Adult
Abstract

Mixed-phenotype acute leukemia (MPAL) is a heterogeneous group of poor-prognosis leukemias with immunophenotypic features of at least two cell lineages. The full spectrum of genetic mutations in this rare disease has not been elucidated, limiting our understanding of disease pathogenesis and our ability to devise targeted therapeutic strategies. Here, we sought to define the mutational landscape of MPAL by performing whole-exome sequencing on samples from 23 adult and pediatric MPAL patients. We identified frequent mutations of epigenetic modifiers, most notably mutations of DNMT3A, in 33% of adult MPAL patients. Mutations of activated signaling pathways, tumor suppressors, and transcription factors were also frequent. Importantly, many of the identified mutations are potentially therapeutically targetable, with agents currently available or in various stages of clinical development. Therefore, the mutational spectrum that we have identified provides potential biological insights and is likely to have clinical relevance for patients with this poor-prognosis disease.

DOI10.1016/j.exphem.2016.05.003
Alternate JournalExp Hematol
PubMed ID27208809
PubMed Central IDPMC4956537
Grant ListR56 DK092883 / DK / NIDDK NIH HHS / United States
P50 CA126752 / CA / NCI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
K12 CA090433 / CA / NCI NIH HHS / United States
T32 DK060445 / DK / NIDDK NIH HHS / United States
R01 CA183252 / CA / NCI NIH HHS / United States
R01 DK092883 / DK / NIDDK NIH HHS / United States

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