Arza-Apalategi Saioa, Heuts Branco M H, Bergevoet Saskia M, Meering Roos, Gilissen Daan, Jansen Pascal W T C, Krippner-Heidenreich Anja, Valk Peter J M, Vermeulen Michiel, Heidenreich Olaf, Haferlach Torsten, Jansen Joop H, Martens Joost H A, van der Reijden Bert A
Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University, Nijmegen, The Netherlands.
Leukemia. 2025 Feb;39(2):371-380. doi: 10.1038/s41375-024-02485-3. Epub 2024 Dec 4.
KMT2A::MLLT3 acute myelomonocytic leukemia (AML) comes in two clinically and biologically different subtypes. One is characterized by inferior outcome, older age, and MECOM oncogene expression. The other is mainly observed in children and young adults, associates with better clinical outcome, but lacks MECOM. To identify cell fate determining transcription factors downstream of KMT2A::MLLT3, we applied a bioinformatic algorithm that integrates gene and enhancer expression from primary MECOM-positive and -negative KMT2A::MLLT3 AML samples. This identified MECOM to be most influential in the MECOM-positive group, while neuronal transcription factor HMX3 was most influential in the MECOM-negative group. In large AML cohorts, HMX3 expression associated with a unique gene expression profile, younger age (p < 0.002) and KMT2A-rearranged and KAT6A-CREBBP leukemia (p < 0.00001). HMX3 was not expressed in other major genetic risk groups and healthy blood cells. RNA-sequencing analyses following forced HMX3 expression in healthy CD34+ cells and its silencing in KMT2A::MLT3 cells showed that HMX3 drives cancer-associated E2F and MYC gene programs (p < 0.001). HMX3 expression in healthy CD34+ cells blocked monocytic but not granulocytic colony formation. Strikingly, HMX3 silencing in KMT2A::MLLT3 patient cells resulted in cell cycle arrest, monocytic differentiation and apoptosis. Thus, the neuronal transcription factor HMX3 is a leukemia-specific vulnerability in KMT2A::MLLT3 AML.
KMT2A::MLLT3急性粒单核细胞白血病（AML）有两种临床和生物学上不同的亚型。一种的特征是预后较差、年龄较大以及MECOM癌基因表达。另一种主要见于儿童和年轻人，临床预后较好，但缺乏MECOM。为了确定KMT2A::MLLT3下游决定细胞命运的转录因子，我们应用了一种生物信息学算法，该算法整合了原发性MECOM阳性和阴性KMT2A::MLLT3 AML样本的基因和增强子表达。这表明MECOM在MECOM阳性组中最具影响力，而神经元转录因子HMX3在MECOM阴性组中最具影响力。在大型AML队列中，HMX3表达与独特的基因表达谱、较年轻的年龄（p < 0.002）以及KMT2A重排和KAT6A-CREBBP白血病相关（p < 0.00001）。HMX3在其他主要遗传风险组和健康血细胞中不表达。在健康CD34+细胞中强制表达HMX3并在KMT2A::MLT3细胞中沉默后进行的RNA测序分析表明，HMX3驱动与癌症相关的E2F和MYC基因程序（p < 0.001）。健康CD34+细胞中HMX3的表达阻断了单核细胞集落形成，但未阻断粒细胞集落形成。引人注目的是，KMT2A::MLLT3患者细胞中HMX3的沉默导致细胞周期停滞、单核细胞分化和凋亡。因此，神经元转录因子HMX3是KMT2A::MLLT3 AML中白血病特异性的脆弱点。
