The molecular mechanisms underlying PHF6-mutation-mediated hematologic malignancies

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Project Summary Somatic mutations of PHF6 are common in diverse hematologic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL, 15%), mixed phenotype acute leukemia (MPAL, 23%), acute myeloid leukemia (AML, 3%), chronic myelomonocytic leukemia (CMML, 5%), and myelodysplastic syndrome (MDS, 3%). PHF6 mutations confer worse overall survival in AML and MPAL. Despite the clinical significance, the molecular mechanisms underlying PHF6 mutation mediated leukemogenesis remain to be explored. The PHF6 genetic lesions in hematological malignancies are largely frameshift and nonsense. The PHF6 gene is located on the X chromosome, and its mutation was thought to be a loss-of-function mutation. However, Phf6 D/D mice do not develop spontaneous hematologic malignancies. A recent study (Ahmed et al. Hum Mol Genet 2023) and our preliminary data showed that truncated PHF6 proteins were detectable in blood cells from three BFLS patients and an HPB ALL cell line with PHF6 truncation mutations. Furthermore, while PHF6 mutations were originally reported predominantly in male T ALL patients, subsequent studies from multiple independent groups have failed to show such a biological sex preference. All these data led us to hypothesize that the truncated PHF6 may exert gain-of-function, in addition to a loss-of-function, in leukemogenesis. We thus generated patient derived mutant Phf6 transgenic (Phf6R274XTg and Phf6R342XTg) mouse models by expressing truncated FLAG-PHF6aa1-273 or -PHF6aa1-342 protein in the hematopoietic lineages. Unlike Phf6 D/D mice, Phf6R274XTg mice and Phf6R342XTg mice developed a spectrum of spontaneous hematologic malignancies, recapitulating the characteristics of PHF6-mutated hematologic malignancy patients. Our goal is to decipher the molecular mechanisms through which the PHF6aa1- 273 leads to leukemogenesis. Three specific aims are proposed. Aim 1: Characterize the hematologic malignancies driven by truncation of PHF6 expression in vivo; Aim 2: Decipher the molecular mechanisms by which truncation of PHF6 expression leads to leukemogenesis; and Aim 3: Explore the therapeutic potential of targeting the truncation of PHF6-enhanced KAT6A/B activity in hematologic malignancies. Our newly generated mouse models, state-of-the-art epigenetic assays, and our collaborative team with longstanding expertise in HSPC biology and hematologic malignancies offer us cutting-edge platforms to successfully carry out the proposed studies. Successful completion of the proposed studies will fill a knowledge gap of the molecular mechanisms underlying PHF6 mutation-mediated hematologic malignancies, which will be pivotal for identifying novel therapeutic targets (s).