Defining 2 biologically and clinically distinct groups in acute leukemia with a mixed phenotype

作     者：Galera, Pallavi Dilip, Deepika Derkach, Andriy Chan, Alexander Zhang, Yanming Persaud, Sonali Mishra, Tanmay Kramer, Kyle Kathpalia, Mahak Liu, Ying Famulare, Christopher Gao, Qi Mata, Douglas A. Arcila, Maria Geyer, Mark B. Stein, Eytan Dogan, Ahmet Roshal, Mikhail Levine, Ross L. Glass, Jacob Xiao, Wenbin 

作者机构：Hematopathology Service Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY United States Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY United States Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY United States Department of Pathology and Laboratory Medicine Cytogenetics Laboratory Memorial Sloan Kettering Cancer Center New York NY United States Molecular Cancer Medicine Service Human Oncogenesis and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY United States Department of Pathology and Laboratory Medicine Diagnostic Molecular Laboratory Memorial Sloan Kettering Cancer Center New York NY United States Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY United States Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY United States Cell Therapy Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY United States 

出 版 物：《Blood》 (Blood)

年 卷 期：2025年第145卷第18期

页      面：2056-2069页

学科分类：0710[理学-生物学] 0831[工学-生物医学工程（可授工学、理学、医学学位）] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 0703[理学-化学] 10[医学] 

基　　金：Equinox Cycle for Survival National Institutes of Health, NIH Alex's Lemonade Stand Foundation for Childhood Cancer, ALSF Cycle for Survival Innovation, (R35 CA197594, K08CA230172) National Cancer Institute, NCI, (P30 CA008748) National Cancer Institute, NCI Cycle for Survival, (P50 CA254838, K08CA267058) Cycle for Survival 

摘      要：A mixed phenotype (MP) is a characteristic of de novo MP acute leukemia (MPAL), but it can also be found in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with MP and define acute myeloid leukemia with MP (AML-MP) and MPAL as 2 distinct groups by characterizing clinical, genetic, and transcriptomic features. Clinically, patients with AML-MP and MPAL were both treated with either AML- or acute lymphoblastic leukemia (ALL)–directed induction regimens. AML-MP has inferior responses (hazard ratio, 12.5;95% confidence interval, 2.72-57.8;P = .001), whereas MPAL has better responses to ALL-directed treatment. Genetically, AML-MP harbors more frequent RUNX1 (23/52 [44%]) and TP53 (12/52 [23.1%]) mutations. In contrast, RUNX1 mutations are less frequent in MPAL (8/35 [23%];P = .01 vs AML-MP) and TP53 mutations as a driver are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment for stemness signatures and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation. Furthermore, AML-MP rarely switches to a lymphoid immunophenotype after treatment, in contrast to MPAL (1/40 [2.5%] vs 10/28 [35.7%];P = .0003). Last, a genomic classification framework is proposed for future studies. Together, these data support the designation of AML-MP as a diagnosis distinct from MPAL and provide novel insights into the pathogenesis and therapies of acute leukemia with MP. © 2025 American Society of Hematology