Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival

Casey D.S. Katerndahl; Lynn M. Heltemes-Harris; Mark J.L. Willette; Christine M. Henzler; Seth Frietze; Rendong Yang; Hilde Schjerven; Kevin A.T. Silverstein; Laura B. Ramsey; Gregory Hubbard; Andrew D. Wells; Roland P. Kuiper; Blanca Scheijen; Frank N. Van Leeuwen; Markus Müschen; Steven M. Kornblau; Michael A. Farrar

doi:10.1038/ni.3716

Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival

Casey D.S. Katerndahl, Lynn M. Heltemes-Harris, Mark J.L. Willette, Christine M. Henzler, Seth Frietze, Rendong Yang, Hilde Schjerven, Kevin A.T. Silverstein, Laura B. Ramsey, Gregory Hubbard, Andrew D. Wells, Roland P. Kuiper, Blanca Scheijen, Frank N. Van Leeuwen, Markus Müschen, Steven M. Kornblau, Michael A. Farrar

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Abstract

The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κ B1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κ B and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4 and IKAROS. Patients with a high ratio of active STAT5 to NF-κ B or IKAROS had more-aggressive disease. Our studies indicate that an imbalance of two opposing transcriptional programs drives B-ALL and suggest that restoring the balance of these pathways might inhibit B-ALL.

Original language	English
Pages (from-to)	694-704
Number of pages	11
Journal	Nature immunology
Volume	18
Issue number	6
DOIs	https://doi.org/10.1038/ni.3716
State	Published - May 18 2017

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Katerndahl, C. D. S., Heltemes-Harris, L. M., Willette, M. J. L., Henzler, C. M., Frietze, S., Yang, R., Schjerven, H., Silverstein, K. A. T., Ramsey, L. B., Hubbard, G., Wells, A. D., Kuiper, R. P., Scheijen, B., Van Leeuwen, F. N., Müschen, M., Kornblau, S. M., & Farrar, M. A. (2017). Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nature immunology, 18(6), 694-704. https://doi.org/10.1038/ni.3716

@article{22e0f81f36d64db6bbf54dbbf75233c1,

title = "Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival",

abstract = "The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κ B1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κ B and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4 and IKAROS. Patients with a high ratio of active STAT5 to NF-κ B or IKAROS had more-aggressive disease. Our studies indicate that an imbalance of two opposing transcriptional programs drives B-ALL and suggest that restoring the balance of these pathways might inhibit B-ALL.",

author = "Katerndahl, {Casey D.S.} and Heltemes-Harris, {Lynn M.} and Willette, {Mark J.L.} and Henzler, {Christine M.} and Seth Frietze and Rendong Yang and Hilde Schjerven and Silverstein, {Kevin A.T.} and Ramsey, {Laura B.} and Gregory Hubbard and Wells, {Andrew D.} and Kuiper, {Roland P.} and Blanca Scheijen and {Van Leeuwen}, {Frank N.} and Markus M{\"u}schen and Kornblau, {Steven M.} and Farrar, {Michael A.}",

year = "2017",

month = may,

day = "18",

doi = "10.1038/ni.3716",

language = "English",

volume = "18",

pages = "694--704",

journal = "Nature immunology",

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Katerndahl, CDS, Heltemes-Harris, LM, Willette, MJL, Henzler, CM, Frietze, S, Yang, R, Schjerven, H, Silverstein, KAT, Ramsey, LB, Hubbard, G, Wells, AD, Kuiper, RP, Scheijen, B, Van Leeuwen, FN, Müschen, M, Kornblau, SM & Farrar, MA 2017, 'Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival', Nature immunology, vol. 18, no. 6, pp. 694-704. https://doi.org/10.1038/ni.3716

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AU - Katerndahl, Casey D.S.

AU - Heltemes-Harris, Lynn M.

AU - Willette, Mark J.L.

AU - Henzler, Christine M.

AU - Frietze, Seth

AU - Yang, Rendong

AU - Schjerven, Hilde

AU - Silverstein, Kevin A.T.

AU - Ramsey, Laura B.

AU - Hubbard, Gregory

AU - Wells, Andrew D.

AU - Kuiper, Roland P.

AU - Scheijen, Blanca

AU - Van Leeuwen, Frank N.

AU - Müschen, Markus

AU - Kornblau, Steven M.

AU - Farrar, Michael A.

PY - 2017/5/18

Y1 - 2017/5/18

N2 - The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κ B1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κ B and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4 and IKAROS. Patients with a high ratio of active STAT5 to NF-κ B or IKAROS had more-aggressive disease. Our studies indicate that an imbalance of two opposing transcriptional programs drives B-ALL and suggest that restoring the balance of these pathways might inhibit B-ALL.

AB - The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κ B1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κ B and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4 and IKAROS. Patients with a high ratio of active STAT5 to NF-κ B or IKAROS had more-aggressive disease. Our studies indicate that an imbalance of two opposing transcriptional programs drives B-ALL and suggest that restoring the balance of these pathways might inhibit B-ALL.

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VL - 18

SP - 694

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JO - Nature immunology

JF - Nature immunology

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ER -

Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival

Abstract

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