Ikaros antagonizes DNA binding by STAT5 in pre-B cells.
The IKZF1 gene, which encodes the Ikaros transcription factor, is frequently deleted or mutated in patients with B-cell precursor acute lymphoblastic leukemias that express oncogenes, like BCR-ABL, which activate the JAK-STAT5 pathway. Ikaros functionally antagonizes the transcriptional programs dow...
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doaj-c85d5f5a417e4dcb8cdba5f4c97162162021-03-04T12:56:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-011511e024221110.1371/journal.pone.0242211Ikaros antagonizes DNA binding by STAT5 in pre-B cells.Beate HeizmannStéphanie Le GrasCélestine SimandPatricia MarchalSusan ChanPhilippe KastnerThe IKZF1 gene, which encodes the Ikaros transcription factor, is frequently deleted or mutated in patients with B-cell precursor acute lymphoblastic leukemias that express oncogenes, like BCR-ABL, which activate the JAK-STAT5 pathway. Ikaros functionally antagonizes the transcriptional programs downstream of IL-7/STAT5 during B cell development, as well as STAT5 activity in leukemic cells. However, the mechanisms by which Ikaros interferes with STAT5 function is unknown. We studied the genomic distribution of Ikaros and STAT5 on chromatin in a murine pre-B cell line, and found that both proteins colocalize on >60% of STAT5 target regions. Strikingly, Ikaros activity leads to widespread loss of STAT5 binding at most of its genomic targets within two hours of Ikaros induction, suggesting a direct mechanism. Ikaros did not alter the level of total or phosphorylated STAT5 proteins, nor did it associate with STAT5. Using sequences from the Cish, Socs2 and Bcl6 genes that Ikaros and STAT5 target, we show that both proteins bind overlapping sequences at GGAA motifs. Our results demonstrate that Ikaros antagonizes STAT5 DNA binding, in part by competing for common target sequences. Our study has implications for understanding the functions of Ikaros and STAT5 in B cell development and transformation.https://doi.org/10.1371/journal.pone.0242211 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Beate Heizmann Stéphanie Le Gras Célestine Simand Patricia Marchal Susan Chan Philippe Kastner |
spellingShingle |
Beate Heizmann Stéphanie Le Gras Célestine Simand Patricia Marchal Susan Chan Philippe Kastner Ikaros antagonizes DNA binding by STAT5 in pre-B cells. PLoS ONE |
author_facet |
Beate Heizmann Stéphanie Le Gras Célestine Simand Patricia Marchal Susan Chan Philippe Kastner |
author_sort |
Beate Heizmann |
title |
Ikaros antagonizes DNA binding by STAT5 in pre-B cells. |
title_short |
Ikaros antagonizes DNA binding by STAT5 in pre-B cells. |
title_full |
Ikaros antagonizes DNA binding by STAT5 in pre-B cells. |
title_fullStr |
Ikaros antagonizes DNA binding by STAT5 in pre-B cells. |
title_full_unstemmed |
Ikaros antagonizes DNA binding by STAT5 in pre-B cells. |
title_sort |
ikaros antagonizes dna binding by stat5 in pre-b cells. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2020-01-01 |
description |
The IKZF1 gene, which encodes the Ikaros transcription factor, is frequently deleted or mutated in patients with B-cell precursor acute lymphoblastic leukemias that express oncogenes, like BCR-ABL, which activate the JAK-STAT5 pathway. Ikaros functionally antagonizes the transcriptional programs downstream of IL-7/STAT5 during B cell development, as well as STAT5 activity in leukemic cells. However, the mechanisms by which Ikaros interferes with STAT5 function is unknown. We studied the genomic distribution of Ikaros and STAT5 on chromatin in a murine pre-B cell line, and found that both proteins colocalize on >60% of STAT5 target regions. Strikingly, Ikaros activity leads to widespread loss of STAT5 binding at most of its genomic targets within two hours of Ikaros induction, suggesting a direct mechanism. Ikaros did not alter the level of total or phosphorylated STAT5 proteins, nor did it associate with STAT5. Using sequences from the Cish, Socs2 and Bcl6 genes that Ikaros and STAT5 target, we show that both proteins bind overlapping sequences at GGAA motifs. Our results demonstrate that Ikaros antagonizes STAT5 DNA binding, in part by competing for common target sequences. Our study has implications for understanding the functions of Ikaros and STAT5 in B cell development and transformation. |
url |
https://doi.org/10.1371/journal.pone.0242211 |
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