title: Mixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DNMT3A and activated signaling genes.
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.
authors.affiliation: Cancer and Hematology Centers, Texas Children's Hospital/Baylor College of Medicine, Houston, TX.
authors.forename: Olive S
authors.initials: OS
authors.lastname: Eckstein
authors.affiliation: Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
authors.forename: Linghua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Pathology and Immunology, Texas Children's Hospital/Baylor College of Medicine, Houston, TX.
authors.forename: Jyotinder N
authors.initials: JN
authors.lastname: Punia
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Cancer and Hematology Centers, Texas Children's Hospital/Baylor College of Medicine, Houston, TX; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX. Electronic address: goodell@bcm.edu.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
authors.affiliation: Cancer and Hematology Centers, Texas Children's Hospital/Baylor College of Medicine, Houston, TX. Electronic address: rachel.rau@bcm.edu.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Rau
mesh_terms: D000293:Adolescent; D000328:Adult; D060965:Clonal Evolution / Q000235:genetics; D016000:Cluster Analysis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D059472:Exome; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A