Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia

Zibo Zhao, Lu Wang, Andrew G. Volk, Noah W. Birch, Kristen L. Stoltz, Elizabeth Thomas Bartom, Stacy A. Marshall, Emily J. Rendleman, Carson M. Nestler, Joseph Shilati, Gary E Schiltz, John D Crispino, Ali Shilatifard*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL chimeras from chromatin. Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations.

Original languageEnglish (US)
Pages (from-to)61-74
Number of pages14
JournalGenes and Development
Volume33
Issue number1-2
DOIs
StatePublished - Jan 1 2019

Fingerprint

Aspartate Ammonia-Lyase
Threonine
Leukemia
Casein Kinase II
Therapeutics
Chromatin
Endopeptidases
Genetic Translocation

Keywords

  • CKII
  • CX-4945
  • KMT2A
  • MLL1
  • Protein stability
  • Regulation of gene expression
  • TASP1
  • Taspase1

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Zhao, Zibo ; Wang, Lu ; Volk, Andrew G. ; Birch, Noah W. ; Stoltz, Kristen L. ; Bartom, Elizabeth Thomas ; Marshall, Stacy A. ; Rendleman, Emily J. ; Nestler, Carson M. ; Shilati, Joseph ; Schiltz, Gary E ; Crispino, John D ; Shilatifard, Ali. / Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia. In: Genes and Development. 2019 ; Vol. 33, No. 1-2. pp. 61-74.
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abstract = "Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL chimeras from chromatin. Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations.",
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Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia. / Zhao, Zibo; Wang, Lu; Volk, Andrew G.; Birch, Noah W.; Stoltz, Kristen L.; Bartom, Elizabeth Thomas; Marshall, Stacy A.; Rendleman, Emily J.; Nestler, Carson M.; Shilati, Joseph; Schiltz, Gary E; Crispino, John D; Shilatifard, Ali.

In: Genes and Development, Vol. 33, No. 1-2, 01.01.2019, p. 61-74.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia

AU - Zhao, Zibo

AU - Wang, Lu

AU - Volk, Andrew G.

AU - Birch, Noah W.

AU - Stoltz, Kristen L.

AU - Bartom, Elizabeth Thomas

AU - Marshall, Stacy A.

AU - Rendleman, Emily J.

AU - Nestler, Carson M.

AU - Shilati, Joseph

AU - Schiltz, Gary E

AU - Crispino, John D

AU - Shilatifard, Ali

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N2 - Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL chimeras from chromatin. Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations.

AB - Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL chimeras from chromatin. Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations.

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KW - CX-4945

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KW - Protein stability

KW - Regulation of gene expression

KW - TASP1

KW - Taspase1

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