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PHF6 and DNMT3A mutations are enriched in distinct subgroups of mixed phenotype acute leukemia with T-lineage differentiation.
Xiao, Wenbin; Bharadwaj, Maheetha; Levine, Max; Farnhoud, Noushin; Pastore, Friederike; Getta, Bartlomiej M; Hultquist, Anne; Famulare, Christopher; Medina, Juan S; Patel, Minal A; Gao, Qi; Lewis, Natasha; Pichardo, Janine; Baik, Jeeyeon; Shaffer, Brian; Giralt, Sergio; Rampal, Raajit; Devlin, Sean; Cimera, Robert; Zhang, Yanming; E Arcila, Maria; Papaemmanuil, Elli; Levine, Ross L; Roshal, Mikhail.
Afiliação
  • Xiao W; Hematopathology Diagnostic Service, Department of Pathology.
  • Bharadwaj M; Center for Hematologic Malignancies.
  • Levine M; Center for Hematologic Malignancies.
  • Farnhoud N; Center for Hematologic Malignancies.
  • Pastore F; Human Oncology and Pathogenesis Program.
  • Getta BM; Bone Marrow Transplant Service, Department of Medicine.
  • Hultquist A; Human Oncology and Pathogenesis Program.
  • Famulare C; Center for Hematologic Malignancies.
  • Medina JS; Center for Hematologic Malignancies.
  • Patel MA; Center for Hematologic Malignancies.
  • Gao Q; Hematopathology Diagnostic Service, Department of Pathology.
  • Lewis N; Hematopathology Diagnostic Service, Department of Pathology.
  • Pichardo J; Hematopathology Diagnostic Service, Department of Pathology.
  • Baik J; Hematopathology Diagnostic Service, Department of Pathology.
  • Shaffer B; Bone Marrow Transplant Service, Department of Medicine.
  • Giralt S; Bone Marrow Transplant Service, Department of Medicine.
  • Rampal R; Leukemia Service, Department of Medicine.
  • Devlin S; Epidemiology and Biostatistics.
  • Cimera R; Cytogenetic Laboratory, Department of Pathology, and.
  • Zhang Y; Cytogenetic Laboratory, Department of Pathology, and.
  • E Arcila M; Molecular Diagnostic Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Papaemmanuil E; Center for Hematologic Malignancies.
  • Levine RL; Epidemiology and Biostatistics.
  • Roshal M; Center for Hematologic Malignancies.
Blood Adv ; 2(23): 3526-3539, 2018 12 11.
Article em En | MEDLINE | ID: mdl-30530780
ABSTRACT
The genetic aberrations that drive mixed phenotype acute leukemia (MPAL) remain largely unknown, with the exception of a small subset of MPALs harboring BCR -ABL1 and MLL translocations. We performed clinicopathologic and genetic evaluation of 52 presumptive MPAL cases at Memorial Sloan Kettering Cancer Center. Only 29 out of 52 (56%) cases were confirmed to be bona fide MPAL according to the 2016 World Heath Organization classification. We identified PHF6 and DNMT3A mutations as the most common recurrent mutations in MPAL, each occurring in 6 out of 26 (23%) cases. These mutations are mutually exclusive of each other and BCR-ABL1/MLL translocations. PHF6- and DNMT3A-mutated MPAL showed marked predilection for T-lineage differentiation (5/6 PHF6 mutated, 6/6 DNMT3A mutated). PHF6-mutated MPAL occurred in a younger patient cohort compared with DNMT3A-mutated cases (median age, 27 years vs 61 years, P < .01). All 3 MPAL cases with both T- and B-lineage differentiation harbored PHF6 mutations. MPAL with T-lineage differentiation was associated with nodal or extramedullary involvement (9/15 [60%] vs 0, P = .001) and a higher relapse incidence (78% vs 22%, P = .017) compared with those without T-lineage differentiation. Sequencing studies on flow-cytometry-sorted populations demonstrated that PHF6 mutations are present in all blast compartments regardless of lineage differentiation with high variant allele frequency, implicating PHF6 as an early mutation in MPAL pathogenesis. In conclusion, PHF6 and DNMT3A mutations are the most common somatic alterations identified in MPAL and appear to define 2 distinct subgroups of MPAL with T-lineage differentiation with inferior outcomes.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Linfócitos T / Leucemia Aguda Bifenotípica / Proteínas de Transporte / DNA (Citosina-5-)-Metiltransferases Tipo de estudo: Prognostic_studies Limite: Adolescent / Adult / Aged / Child / Child, preschool / Female / Humans / Infant / Male / Middle aged Idioma: En Revista: Blood Adv Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Linfócitos T / Leucemia Aguda Bifenotípica / Proteínas de Transporte / DNA (Citosina-5-)-Metiltransferases Tipo de estudo: Prognostic_studies Limite: Adolescent / Adult / Aged / Child / Child, preschool / Female / Humans / Infant / Male / Middle aged Idioma: En Revista: Blood Adv Ano de publicação: 2018 Tipo de documento: Article