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

43 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

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Keywords

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

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Cite this

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

Liang, Kaiwei ; Volk, Andrew G. ; Haug, J. S. ; Marshall, Stacy A. ; Woodfin, Ashley R. ; Bartom, Elizabeth T. ; Gilmore, Joshua M. ; Florens, Laurence ; Washburn, Michael P. ; Sullivan, Kelly D. ; Espinosa, Joaquin M. ; Cannova, Joseph ; Zhang, Jiwang ; Smith, Edwin R. ; Crispino, John D. ; Shilatifard, Ali. / Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia. In: Cell. 2017 ; Vol. 168, No. 1-2. pp. 59-72.e13.

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

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Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia. / Liang, Kaiwei; Volk, Andrew G.; Haug, J. S.; Marshall, Stacy A.; Woodfin, Ashley R.; Bartom, Elizabeth T.; Gilmore, Joshua M.; Florens, Laurence; Washburn, Michael P.; Sullivan, Kelly D.; Espinosa, Joaquin M.; Cannova, Joseph; Zhang, Jiwang; Smith, Edwin R.; Crispino, John D.; Shilatifard, Ali.

In: Cell, Vol. 168, No. 1-2, 12.01.2017, p. 59-72.e13.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

AU - Liang, Kaiwei

AU - Volk, Andrew G.

AU - Haug, J. S.

AU - Marshall, Stacy A.

AU - Woodfin, Ashley R.

AU - Bartom, Elizabeth T.

AU - Gilmore, Joshua M.

AU - Florens, Laurence

AU - Washburn, Michael P.

AU - Sullivan, Kelly D.

AU - Espinosa, Joaquin M.

AU - Cannova, Joseph

AU - Zhang, Jiwang

AU - Smith, Edwin R.

AU - Crispino, John D.

AU - Shilatifard, Ali

PY - 2017/1/12

Y1 - 2017/1/12

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.

AB - 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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10.1016/j.cell.2016.12.011