PAX5 is part of a functional transcription factor network targeted in lymphoid leukemia

Abstract

One of the most frequently mutated proteins in human B-lineage leukemia is the transcription factor PAX5. These mutations often result in partial rather than complete loss of function of the transcription factor. While the functional dose of PAX5 has a clear connection to human malignancy, there is limited evidence for that heterozygote loss of PAX5 have a dramatic effect on the development and function of B-cell progenitors. One possible explanation comes from the finding that PAX5 mutated B-ALL often display complex karyotypes and additional mutations. Thus, PAX5 might be one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we used BioID technology to isolate proteins associated with this transcription factor in the living cell. This identified 239 proteins out of which several could be found mutated in human B-ALL. Most prominently we identified the commonly mutated IKZF1 and RUNX1, involved in the formation of ETV6-AML1 fusion protein, among the interaction partners. ChIP- as well as PLAC-seq analysis supported the idea that these factors share a multitude of target genes in human B-ALL cells. Gene expression analysis of mouse models and primary human leukemia suggested that reduced function of PAX5 increased the ability of an oncogenic form of IKZF1 or ETV6-AML to modulate gene expression. Our data reveals that PAX5 belong to a regulatory network frequently targeted by multiple mutations in B-ALL shedding light on the molecular interplay in leukemia cells.

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1-positive pediatric leukemia identifies drug-targetable transcription factor activities

“…S3d, targets ranked by Npred). ChIP-seq validated genes include known PAX5 targets from confirmed regulatory loops ( EBF1 , IRF4 , BACH2 ) and B cell maturation pathways [ 81 – 83 ]. The high agreement of ATAC-seq motif enrichment and the verified TF binding at target gene set loci based on ChIP-seq provides evidence that the TF activity scoring reflects bona fide active regulatory interactions.…”

Genetic Profiling of Advanced Melanoma: Candidate Mutations for Predicting Sensitivity and Resistance to Targeted Therapy

“…This gene, which encodes paired box transcription factor, regulates B cell differentiation. Alterations in its expression contribute to neoplastic transformation [48]. To our knowledge, only two reports have associated it with melanoma biology [23,26].…”

Targeting Lymphotoxin Beta and Paired Box 5: a potential therapeutic strategy for soft tissue sarcoma metastasis

“…Paired Box 5 (PAX5) encodes a member of the PAX family and functions as a TF through a DNA-binding motif, which is also known as a paired box. Paired box transcription factors are vital regulators of early organ development and tissue differentiation, and alterations in their expression are considered catalysts in neoplastic transformation [36]. Previous studies revealed that as a B-lymphoid transcription factor, PAX5 was downregulated in over 80% of pre-B cell acute lymphoblastic leukaemia (ALL), and its downregulation in lymphoid neoplasms was associated with promoter hypermethylation and poor clinical outcomes [37,38].…”