Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia

Shujun Liu; Lai Chu Wu; Jiuxia Pang; Ramasamy Santhanam; Sebastian Schwind; Yue Zhong Wu; Christopher J. Hickey; Jianhua Yu; Heiko Becker; Kati Maharry; Michael D. Radmacher; Chenglong Li; Susan P. Whitman; Anjali Mishra; Nicole Stauffer; Anna M. Eiring; Roger Briesewitz; Robert A. Baiocchi; Kenneth K. Chan; Peter Paschka; Michael A. Caligiuri; John C. Byrd; Carlo M. Croce; Clara D. Bloomfield; Danilo Perrotti; Ramiro Garzon; Guido Marcucci

doi:10.1016/j.ccr.2010.03.008

Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia

Shujun Liu, Lai Chu Wu, Jiuxia Pang, Ramasamy Santhanam, Sebastian Schwind, Yue Zhong Wu, Christopher J. Hickey, Jianhua Yu, Heiko Becker, Kati Maharry, Michael D. Radmacher, Chenglong Li, Susan P. Whitman, Anjali Mishra, Nicole Stauffer, Anna M. Eiring, Roger Briesewitz, Robert A. Baiocchi, Kenneth K. Chan, Peter PaschkaMichael A. Caligiuri, John C. Byrd, Carlo M. Croce, Clara D. Bloomfield, Danilo Perrotti, Ramiro Garzon, Guido Marcucci

Research output: Contribution to journal › Article › peer-review

237 Scopus citations

Abstract

The biologic and clinical significance of KIT overexpression that associates with KIT gain-of-function mutations occurring in subsets of acute myeloid leukemia (AML) (i.e., core binding factor AML) is unknown. Here, we show that KIT mutations lead to MYC-dependent miR-29b repression and increased levels of the miR-29b target Sp1 in KIT-driven leukemia. Sp1 enhances its own expression by participating in a NFκB/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NFκB and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFκB/HDAC/miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFκB/HDAC complex or synthetic miR-29b treatment in KIT-driven AML.

Original language	English (US)
Pages (from-to)	333-347
Number of pages	15
Journal	Cancer Cell
Volume	17
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2010.03.008
State	Published - Apr 13 2010
Externally published	Yes

Bibliographical note

Funding Information:
Supported in part by National Cancer Institute (Bethesda, MD) grants CA102031, CA077658, CA101140, CA140158, CA114725, the Harry T. Mangurian Jr. Foundation Leukemia Research Fund, the Coleman Leukemia Research Foundation, the Sidney Kimmel Cancer Research Foundation, and the Deutsche Krebshilfe (Dr. Mildred Scheel Foundation for Cancer Research). We thank Dr. Clara Nervi for providing the SKNO-1 cell line, Drs. Kathryn G. Roberts and Nicole Verrills for providing FDC-P1 cell lines, and J. Kearney-Bryan and Drs. R. Klisovic and Zhongfa Liu for their technical support.

Keywords

CELLCYCLE
DNA
RNA

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1016/j.ccr.2010.03.008

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Liu, S., Wu, L. C., Pang, J., Santhanam, R., Schwind, S., Wu, Y. Z., Hickey, C. J., Yu, J., Becker, H., Maharry, K., Radmacher, M. D., Li, C., Whitman, S. P., Mishra, A., Stauffer, N., Eiring, A. M., Briesewitz, R., Baiocchi, R. A., Chan, K. K., ... Marcucci, G. (2010). Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia. Cancer Cell, 17(4), 333-347. https://doi.org/10.1016/j.ccr.2010.03.008

Liu, S, Wu, LC, Pang, J, Santhanam, R, Schwind, S, Wu, YZ, Hickey, CJ, Yu, J, Becker, H, Maharry, K, Radmacher, MD, Li, C, Whitman, SP, Mishra, A, Stauffer, N, Eiring, AM, Briesewitz, R, Baiocchi, RA, Chan, KK, Paschka, P, Caligiuri, MA, Byrd, JC, Croce, CM, Bloomfield, CD, Perrotti, D, Garzon, R & Marcucci, G 2010, 'Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia', Cancer Cell, vol. 17, no. 4, pp. 333-347. https://doi.org/10.1016/j.ccr.2010.03.008

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title = "Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia",

abstract = "The biologic and clinical significance of KIT overexpression that associates with KIT gain-of-function mutations occurring in subsets of acute myeloid leukemia (AML) (i.e., core binding factor AML) is unknown. Here, we show that KIT mutations lead to MYC-dependent miR-29b repression and increased levels of the miR-29b target Sp1 in KIT-driven leukemia. Sp1 enhances its own expression by participating in a NFκB/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NFκB and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFκB/HDAC/miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFκB/HDAC complex or synthetic miR-29b treatment in KIT-driven AML.",

keywords = "CELLCYCLE, DNA, RNA",

author = "Shujun Liu and Wu, {Lai Chu} and Jiuxia Pang and Ramasamy Santhanam and Sebastian Schwind and Wu, {Yue Zhong} and Hickey, {Christopher J.} and Jianhua Yu and Heiko Becker and Kati Maharry and Radmacher, {Michael D.} and Chenglong Li and Whitman, {Susan P.} and Anjali Mishra and Nicole Stauffer and Eiring, {Anna M.} and Roger Briesewitz and Baiocchi, {Robert A.} and Chan, {Kenneth K.} and Peter Paschka and Caligiuri, {Michael A.} and Byrd, {John C.} and Croce, {Carlo M.} and Bloomfield, {Clara D.} and Danilo Perrotti and Ramiro Garzon and Guido Marcucci",

note = "Funding Information: Supported in part by National Cancer Institute (Bethesda, MD) grants CA102031, CA077658, CA101140, CA140158, CA114725, the Harry T. Mangurian Jr. Foundation Leukemia Research Fund, the Coleman Leukemia Research Foundation, the Sidney Kimmel Cancer Research Foundation, and the Deutsche Krebshilfe (Dr. Mildred Scheel Foundation for Cancer Research). We thank Dr. Clara Nervi for providing the SKNO-1 cell line, Drs. Kathryn G. Roberts and Nicole Verrills for providing FDC-P1 cell lines, and J. Kearney-Bryan and Drs. R. Klisovic and Zhongfa Liu for their technical support. ",

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AU - Liu, Shujun

AU - Wu, Lai Chu

AU - Pang, Jiuxia

AU - Santhanam, Ramasamy

AU - Schwind, Sebastian

AU - Wu, Yue Zhong

AU - Hickey, Christopher J.

AU - Yu, Jianhua

AU - Becker, Heiko

AU - Maharry, Kati

AU - Radmacher, Michael D.

AU - Li, Chenglong

AU - Whitman, Susan P.

AU - Mishra, Anjali

AU - Stauffer, Nicole

AU - Eiring, Anna M.

AU - Briesewitz, Roger

AU - Baiocchi, Robert A.

AU - Chan, Kenneth K.

AU - Paschka, Peter

AU - Caligiuri, Michael A.

AU - Byrd, John C.

AU - Croce, Carlo M.

AU - Bloomfield, Clara D.

AU - Perrotti, Danilo

AU - Garzon, Ramiro

AU - Marcucci, Guido

N1 - Funding Information: Supported in part by National Cancer Institute (Bethesda, MD) grants CA102031, CA077658, CA101140, CA140158, CA114725, the Harry T. Mangurian Jr. Foundation Leukemia Research Fund, the Coleman Leukemia Research Foundation, the Sidney Kimmel Cancer Research Foundation, and the Deutsche Krebshilfe (Dr. Mildred Scheel Foundation for Cancer Research). We thank Dr. Clara Nervi for providing the SKNO-1 cell line, Drs. Kathryn G. Roberts and Nicole Verrills for providing FDC-P1 cell lines, and J. Kearney-Bryan and Drs. R. Klisovic and Zhongfa Liu for their technical support.

PY - 2010/4/13

Y1 - 2010/4/13

N2 - The biologic and clinical significance of KIT overexpression that associates with KIT gain-of-function mutations occurring in subsets of acute myeloid leukemia (AML) (i.e., core binding factor AML) is unknown. Here, we show that KIT mutations lead to MYC-dependent miR-29b repression and increased levels of the miR-29b target Sp1 in KIT-driven leukemia. Sp1 enhances its own expression by participating in a NFκB/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NFκB and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFκB/HDAC/miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFκB/HDAC complex or synthetic miR-29b treatment in KIT-driven AML.

AB - The biologic and clinical significance of KIT overexpression that associates with KIT gain-of-function mutations occurring in subsets of acute myeloid leukemia (AML) (i.e., core binding factor AML) is unknown. Here, we show that KIT mutations lead to MYC-dependent miR-29b repression and increased levels of the miR-29b target Sp1 in KIT-driven leukemia. Sp1 enhances its own expression by participating in a NFκB/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NFκB and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFκB/HDAC/miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFκB/HDAC complex or synthetic miR-29b treatment in KIT-driven AML.

KW - CELLCYCLE

KW - DNA

KW - RNA

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AN - SCOPUS:77950480186

SN - 1535-6108

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SP - 333

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JO - Cancer Cell

JF - Cancer Cell

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ER -

Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia

Abstract

Bibliographical note

Keywords

UN SDGs

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