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
Hematopathology Service Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY.
Blood. 2025 May 1;145(18):2056-2069. doi: 10.1182/blood.2024026273.
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.
混合表型（MP）是初发MP急性白血病（MPAL）的一个特征，但也可见于其他白血病。它带来了重大的分类和管理难题。在此，我们报告了一大群患有MP的急性白血病患者，并通过对临床、遗传和转录组特征进行表征，将MP急性髓系白血病（AML-MP）和MPAL定义为两个不同的组。临床上，AML-MP和MPAL患者均接受了AML或急性淋巴细胞白血病（ALL）导向的诱导方案治疗。AML-MP的反应较差（风险比，12.5；95%置信区间，2.72 - 57.8；P = .001），而MPAL对ALL导向治疗的反应较好。在基因方面，AML-MP中RUNX1（23/52 [44%]）和TP53（12/52 [23.1%]）突变更为常见。相比之下，RUNX1突变在MPAL中较少见（8/35 [23%]；与AML-MP相比，P = .01），并且作为驱动因素的TP53突变在MPAL中几乎不存在。在转录方面，AML-MP显示干性特征富集，而对髓系和淋巴系分化至关重要的转录因子相对缺乏。此外，与MPAL（1/40 [2.5%] 对 10/28 [35.7%]；P = .0003）相反，AML-MP在治疗后很少转变为淋巴免疫表型。最后，提出了一个基因组分类框架以供未来研究。总之，这些数据支持将AML-MP指定为与MPAL不同的诊断，并为MP急性白血病的发病机制和治疗提供了新的见解。
