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

• Published in: PLoS genetics Vol. 15; no. 8; p. e1008280
• Main Authors: Okuyama, Kazuki, Strid, Tobias, Kuruvilla, Jacob, Somasundaram, Rajesh, Cristobal, Susana, Smith, Emma, Prasad, Mahadesh, Fioretos, Thoas, Lilljebjörn, Henrik, Soneji, Shamit, Lang, Stefan, Ungerbäck, Jonas, Sigvardsson, Mikael
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.08.2019; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; AML1 protein; Animal models; Animals; B cells; Basic Medicine; Bioinformatics; Biology and life sciences; Chromosomes; Collaboration; Core Binding Factor Alpha 2 Subunit - genetics; Disease Models, Animal; Displays (Marketing); DNA binding proteins; Funding; Fusion protein; Gene expression; Gene Expression Regulation; Gene Expression Regulation, Leukemic; Gene Regulatory Networks - genetics; Genes; Genetic aspects; Genetics; Genomes; Health aspects; Hematology; Humans; Ikaros Transcription Factor - genetics; Karyotypes; Leukemia; Lymphatic leukemia; Lymphocytes B; Lymphocytic leukemia; Malignancy; Medical and Health Sciences; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicine; Medicine and Health Sciences; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Knockout; Mutation; Oncogene Proteins, Fusion - genetics; Pax5 protein; PAX5 Transcription Factor - genetics; Pipelines; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cells, B-Lymphoid; Primary Cell Culture; Proteins; Research and Analysis Methods; Runx1 protein; Software; Stem cells; Supervision; Technology; Transcription factors; Tumor Cells, Cultured; Sweden
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008280

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.