PHF6 keeps hematopoietic lineage development in check [ALLSIL]

Analysis of the mutational landscape of various hematological malignancies has shown that key regulators implicated in lineage commitment and differentiation are frequently implicated in leukemic transformation. In T-cell acute lymphoblastic leukemia, the role of various oncogenic and tumor suppressing transcription factors has been investigated. More recently, an exceptional high prevalence of mutations affecting epigenetic modifiers in T-ALL has also been noted. In order to understand the exact contribution of such lesions to normal differentiation and oncogenic transformation, further functional characterization of this subclass of proteins is warranted. PHF6 is one of these key epigenetic players, which was described as a frequently mutated and deleted novel tumor suppressor in T-ALL. In a first step towards unraveling the role of PHF6 in normal and malignant hematopoiesis, we characterized the function of PHF6 in both normal T-cell differentiation and other hematopoietic lineages as a prelude to understand its contribution to leukemogenesis. Here, we show for the first time that PHF6 controlled epigenetic regulation positively controls a NOTCH1 gene signature and the effects observed on T-lineage differentiation seem to be additive with Notch1. In this study, we show for the first time that PHF6 is a master regulator of early hematopoietic differentiation along the T-cell, B-cell, myeloid and NK-cell lineages. Gene expression was measured in ALL-SIL T-ALL lymphoblasts upon electroporation with a control or PHF6 targeting siRNA. Cells were collected after 96h post-electroporation. This was performed for 3 independent biological replicates.