PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes

Abstract

Developmental and lineage plasticity have been observed in numerous malignancies and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the plant homeodomain finger protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B-cell-and T-cell-specific factors. Additionally, Phf6KO cells show significant downregulation of genes involved in the development and function of normal B cells, show up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition.

PHF6 promotes non‐homologous end joining and G2 checkpoint recovery

“…In contrast to PHF3, ACTL6A and BRD2 were accumulating at laserinduced DNA lesions (Fig EV2B). Interestingly, another hit from our screen, the transcriptional regulator PHF6 (PHD finger 6), was found to be mutated in Börjeson-Forssman-Lehmann syndrome, which is a rare X-linked genetic disorder characterized by mental retardation, craniopharyngeal abnormalities, and hematological cancers [39][40][41][42][43][44]. This is in accordance with a recent study showing that BRD2 is recruited to nuclease-induced DSBs [38].…”

“…Moreover, PHF6 localizes within the nucleolus, where it is important for the repression of ribosomal DNA transcription [46,47]. Mass spectrometry studies have indicated that PHF6 might be part of the NuRD complex, an ATP-dependent chromatin remodeler that also harbors histone deacetylation activity [42,43,50]. On that note, ribosomal RNA synthesis is inhibited after DNA damage, and this response is mediated by, besides PHF6, DNA-PK, and PARP1, factors promoting the repair of DSBs through NHEJ [48,49].…”

“…Depletion of PHF6 was reported to lead to increased transcription of ribosomal DNA, resulting in a DNA damage-dependent stabilization of p53 and subsequent cell cycle arrest [46]. In addition to being involved in the regulation of transcription [43], the chromatin-remodeling activity of the NuRD complex has also been shown to be important for the DDR [51][52][53], in which the complex so far has been implicated in the repair of DSBs through HR [54][55][56][57]. Mass spectrometry studies have indicated that PHF6 might be part of the NuRD complex, an ATP-dependent chromatin remodeler that also harbors histone deacetylation activity [42,43,50].…”

Phenotype switch in acute lymphoblastic leukaemia associated with 3 years of persistent CAR T cell directed‐CD19 selective pressure

“…Lastly, this patient's tumour also carried a probable pathogenic truncating mutation in the transcription factor PHF6. Loss of function mutations in PHF6 have recently been implicated in leukemogenesis and lineage plasticity (Soto‐Feliciano et al , ). Although previously described in AML and T‐ALL, there are no prior studies that identify this mutation in B‐ALL.…”

“…Although previously described in AML and T‐ALL, there are no prior studies that identify this mutation in B‐ALL. Most intriguing, Soto‐Feliciano et al () described a mouse model of phenotype plasticity in leukaemic cells from PHF6 ‐knockout mice induced by the oncogene BCR ‐ ABL1, further illustrating the importance of this transcription factor in navigating selection pressure.…”