Dataset Information

PAX5 belongs to a functional transcription factor network commonly targeted in B-lineage leukemia

ABSTRACT: One of the most frequently mutated proteins in human B-lineage leukemia is the transcription factor PAX5 mutated in about one third of all cases. While reduced function of PAX5 has a clear link to human malignancy there is limited evidence for that the this directly impact the development of function of B-cell progenitors. One possible explanation to this comes from the finding that PAX5 mutated B-ALL display complex karyotypes and additional mutations. This suggestsindicating that PAX5 might be one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we identified proteins associated with this transcription factor using BioID technology. This identified more than 239 proteins several of which could be found mutated in human B-ALL. Most prominently we identified IKZF1, commonly mutated, and RUNX1, involved in the formation of ETV6-AML1 fusion protein formation, among the interaction partners. CHIPChIP-seq as well as PLAC-seq analysis supported the idea that these factors share regulatory elements in human B-ALL cells. Gene expression and mutation analysis of both mouse models and primary human leukemia suggested that these factors form a functional gene regulatory network targeted by multiple mutations in human B-ALL. In summary, we here present a model where a transcription factor can work through redeployment of other factors and not only through sites that it binds itself.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126300 | GEO | 2019/07/13

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:PAX5, one of nine members of the mammalian paired box (PAX) family of transcription factors, plays an important role in B cell development. Approximately one-third of individuals with pre-B acute lymphoblastic leukemia (ALL) acquire heterozygous inactivating mutations of PAX5 in malignant cells, and heterozygous germline loss-offunction PAX5 mutations cause autosomal dominant predisposition to ALL. At least in mice, Pax5 is required for pre-B cell maturation, and leukemic remission occurs when Pax5 expression is restored in a Pax5-deficient mouse model of ALL. Together, these observations indicate that PAX5 deficiency reversibly drives leukemogenesis. PAX5 and its two most closely related paralogs, PAX2 and PAX8, which are not mutated in ALL, exhibit overlapping expression and function redundantly during embryonic development. However, PAX5 alone is expressed in lymphocytes, while PAX2 and PAX8 are predominantly specific to kidney and thyroid, respectively. We show that forced expression of PAX2 or PAX8 complements PAX5 loss-of-function mutation in ALL cells as determined by modulation of PAX5 target genes, restoration of immunophenotypic and morphological differentiation, and, ultimately, reduction of replicative potential. Activation of PAX5 paralogs, PAX2 or PAX8, ordinarily silenced in lymphocytes, may therefore represent a novel approach for treating PAX5-deficient ALL. In pursuit of this strategy, we took advantage of the fact that, in kidney, PAX2 is upregulated by extracellular hyperosmolarity. We found that hyperosmolarity, at potentially clinically achievable levels, transcriptionally activates endogenous PAX2 in ALL cells via a mechanism dependent on NFAT5, a transcription factor coordinating response to hyperosmolarity. We also found that hyperosmolarity upregulates residual wild type PAX5 expression in ALL cells and modulates gene expression, including in PAX5-mutant primary ALL cells. These findings specifically demonstrate that osmosensing pathways may represent a new therapeutic target for ALL and more broadly point toward the possibility of using gene paralogs to rescue mutations driving cancer and other diseases.

Dataset Information

PAX5 belongs to a functional transcription factor network commonly targeted in B-lineage leukemia

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets