Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Okuyama, Kazuki ; Strid, Tobias LU ; Kuruvilla, Jacob LU ; Somasundaram, Rajesh ; Cristobal, Susana ; Smith, Emma LU ; Prasad, Mahadesh ; Fioretos, Thoas LU ; Lilljebjörn, Henrik LU orcid and Soneji, Shamit LU , et al. (2019) In PLoS Genetics 15(8).
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Genetics
volume
15
issue
8
article number
e1008280
publisher
Public Library of Science (PLoS)
external identifiers
  • scopus:85071353186
  • pmid:31381561
ISSN
1553-7404
DOI
10.1371/journal.pgen.1008280
language
English
LU publication?
yes
id
ca867c35-ae5f-43e3-af19-276b2b7df043
date added to LUP
2019-09-09 09:47:37
date last changed
2024-11-13 17:04:56
@article{ca867c35-ae5f-43e3-af19-276b2b7df043,
  abstract     = {{<p>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.</p>}},
  author       = {{Okuyama, Kazuki and Strid, Tobias and Kuruvilla, Jacob and Somasundaram, Rajesh and Cristobal, Susana and Smith, Emma and Prasad, Mahadesh and Fioretos, Thoas and Lilljebjörn, Henrik and Soneji, Shamit and Lang, Stefan and Ungerbäck, Jonas and Sigvardsson, Mikael}},
  issn         = {{1553-7404}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS Genetics}},
  title        = {{PAX5 is part of a functional transcription factor network targeted in lymphoid leukemia}},
  url          = {{http://dx.doi.org/10.1371/journal.pgen.1008280}},
  doi          = {{10.1371/journal.pgen.1008280}},
  volume       = {{15}},
  year         = {{2019}},
}