Role of PHF6 in Normal Hematopoiesis and hematopoietic stem cell biology

Project: Research project

Description

The plant homeodomain finger 6 (PHF6) is a member of the plant homeodomain (PHD)-like finger family genes. PHF6 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL, ~15%) and various myeloid malignancies including acute myeloid leukemia (AML, ~3%), myelodysplastic syndrome (MDS, ~3%) and chronic myelomonocytic leukemia (CMML, ~5%). Interestingly, the PHF6 genetic lesions in hematological malignancies are largely frameshift and nonsense mutations distributed throughout the gene, indicating that these PHF6 mutations likely result in the loss of WT PHF6 and the expression of a truncated PHF6. Furthermore, clinical studies showed that PHF6 mutations confer worse overall survival in patients with MDS and AML. Despite the clinical significance of PHF6 mutations in hematologic neoplasms, the role of PHF6 in normal hematopoiesis and the impact of its mutations on the hematopoietic stem/progenitor cell (HSPC) functions remain unknown. In addition, it is not known whether the truncated-PHF6 leads to a bona fide loss-of- function or exerts a gain-of-function in hematopoiesis. Given the fact that PHF6 is located on the X chromosome and its mutations are male dominant, we hypothesize that the PHF6 mutations confer a gain-of- function in vivo. We therefore generated a conditional Phf6 knock-out (Phf6flox) mouse model to determine the role of PHF6 in normal hematopoiesis and whether loss of Phf6 affect HSPC cell fate and functions. In addition, we also established two transgenic mice expressing two different patient-derived truncated PHF6 (Phf6R274X and Phf6R342XTg) solely in hematopoiesis to determine the impact of truncated PHF6 on HSPC activities. Our preliminary data showed that Phf6-loss in mice increase hematopoietic stem cell self-renewal, indicating that PHF6 plays an important role in HSC regulation. We also found that PHF6 truncation expression confer a gain-of-function to promote HSC self-renewal. With these models in hand, we will determine the hematological phenotypes of mice with combined Phf6-inactivation and expression of truncated PHF6 in hematopoiesis, and define the cellular and molecular mechanisms by which PHF6 and its truncated mutations impact on HSPC functions. Mechanistically, we will identify key PHF6 and truncated PHF6 binding partners and determine the importance of these interactions to their genomic localization and common target gene expression in HSPCs. These studies will greatly improve our understanding for the role of PHF6 in normal hematopoiesis as well as the impact of PHF6 mutations on HSPC functions. Moreover, these PHF6 mutant models offer a biological platform in which drugs can be tested and developed. These studies are timely and fundamentally important for advancing our knowledge on PHF6 in normal hematopoiesis and HSPC biology.
StatusActive
Effective start/end date7/15/196/30/22

Funding

  • National Institutes of Health: $307,000.00

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Hematopoiesis
Hematopoietic Stem Cells
Cell Biology
Mutation
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Hematologic Neoplasms
Leukemia, Myelomonocytic, Chronic