Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Kaiwei Liang; Andrew G. Volk; J. S. Haug; Stacy A. Marshall; Ashley R. Woodfin; Elizabeth T. Bartom; Joshua M. Gilmore; Laurence Florens; Michael P. Washburn; Kelly D. Sullivan; Joaquin M. Espinosa; Joseph Cannova; Jiwang Zhang; Edwin R. Smith; John D. Crispino; Ali Shilatifard

doi:10.1016/j.cell.2016.12.011

Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Kaiwei Liang, Andrew G. Volk, J. S. Haug, Stacy A. Marshall, Ashley R. Woodfin, Elizabeth T. Bartom, Joshua M. Gilmore, Laurence Florens, Michael P. Washburn, Kelly D. Sullivan, Joaquin M. Espinosa, Joseph Cannova, Jiwang Zhang, Edwin R. Smith, John D. Crispino, Ali Shilatifard^*

^*Corresponding author for this work

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

102 Scopus citations

Abstract

Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex. Pharmacologically inhibiting this pathway substantially delays progression, and it improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and, therefore, relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.

Original language	English (US)
Pages (from-to)	59-72.e13
Journal	Cell
Volume	168
Issue number	1-2
DOIs	https://doi.org/10.1016/j.cell.2016.12.011
State	Published - Jan 12 2017

Funding

We thank the Molecular Biology core facility at the Stowers Institute for creating and sequencing libraries for next-generation sequencing. We thank Dr. El Bachir Affar (University of Montreal) and Dr. George R. Stark (Cleveland Clinic) for sharing reagents. We thank Malcolm Cook for aligning shRNA library sequences and Laura Shilatifard for editorial assistance. This work was performed to fulfill, in part, requirements for the Ph.D. thesis research of K.L. as a student with the Open University. This study was supported by the Samuel Waxman Cancer Research Foundation to J.D.C. and NIH grants CA117907 to J.M.E., CA101774 to J.D.C., CA211428 to E.R.S., and R35CA197569 to A.S.

Keywords

IRAK1
IRAK4
MLL
MLL chimera
SEC
UBE2O
interleukin-1
mixed-lineage leukemia
super elongation complex
wild-type MLL

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

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

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10.1016/j.cell.2016.12.011

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Liang, K., Volk, A. G., Haug, J. S., Marshall, S. A., Woodfin, A. R., Bartom, E. T., Gilmore, J. M., Florens, L., Washburn, M. P., Sullivan, K. D., Espinosa, J. M., Cannova, J., Zhang, J., Smith, E. R., Crispino, J. D., & Shilatifard, A. (2017). Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia. Cell, 168(1-2), 59-72.e13. https://doi.org/10.1016/j.cell.2016.12.011

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abstract = "Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex. Pharmacologically inhibiting this pathway substantially delays progression, and it improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and, therefore, relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.",

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N2 - Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex. Pharmacologically inhibiting this pathway substantially delays progression, and it improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and, therefore, relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.

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Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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