PHF6 as a novel interactor of the transcriptional co-regulator LMO2 in T-Cell acute lymphoblastic leukaemia (T-ALL) and myeloid differentiation

Abstract

The LIM-Only protein 2 (LMO2) is a transcriptional co-regulator that forms a multi-protein complex with TAL1, GATA, and LDB1. This complex regulates transcription from the onset of haematopoietic development and differentiation. However, LMO2 is normally downregulated during T-cell development. Genetic abnormalities that trigger the aberrant expression of LMO2 and other members of the complex lead to T-cell acute lymphoblastic leukaemia (T-ALL). The components of the LMO2 complex are not widely explored in T-ALL and its functions are not fully characterised in this type of leukaemia. Through proteomic analysis we identified the Plant homeodomain zinc finger protein 6 (PHF6) as a novel interactor of LMO2. Mutations of PHF6 have been found to occur in several types of leukaemia including T-ALL. We show a functional interaction between PHF6 and the LMO2 complex members by genome-wide approaches in T-ALL. These outcomes indicated that the LMO2 complex recruits PHF6 to the DNA and regulates gene expression. Importantly, we identified many genes of transcription factors, which are involved in haematopoietic stem cell (HSC) self-renewal and development of early T-cell progenitors, as putative targets of LMO2/PHF6 complex, providing compelling indications of an oncogenic mechanism of the complex. Additionally, Phf6 gene knockdown in myeloid cells suggested a role for PHF6 in the differentiation of this lineage. Finally, loss of PHF6 and LMO2 caused chromosomal instability and signs of DNA damage in these cells, implying a possible function in chromosome and genome stability.