ECS ASB2 mediates MLL degradation during hematopoietic differentiation

Jingya Wang, Andrew G. Muntean, Jay Hess

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Mixed lineage leukemia (MLL) is a key epigenetic regulator of normal hematopoietic development and chromosomal translocations involving MLL are one of the most common genetic alterations in human leukemia. Here we show that ASB2, a component of the ECS ASB E3 ubiquitin ligase complex, mediates MLL degradation through interaction with the PHD/Bromodomain region of MLL. Forced expression of ASB2 degrades MLL and reduces MLL transactivation activity. In contrast, the MLL-AF9 fusion protein does not interact with ASB2 and is resistant to ASB2 mediated degradation. Increased expression of ASB2 during hematopoietic differentiation is associated with decreased levels of MLL protein and down-regulation of MLL target genes. Knockdown of ASB2 leads to increased expression of HOXA9 and delayed cell differentiation. Our data support a model whereby ASB2 contributes to hematopoietic differentiation, in part, through MLL degradation and HOX gene down-regulation. Moreover, deletion of the PHD/Bromo region renders MLL fusion proteins resistant to ASB2-mediated degradation and may contribute to leukemogenesis.

Original languageEnglish (US)
Pages (from-to)1151-1161
Number of pages11
JournalBlood
Volume119
Issue number5
DOIs
StatePublished - Feb 2 2012
Externally publishedYes

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Leukemia
Degradation
Myeloid-Lymphoid Leukemia Protein
Fusion reactions
Genes
Ubiquitin-Protein Ligases
Proteins
Down-Regulation
Genetic Translocation
Epigenomics
Transcriptional Activation
Cell Differentiation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

ECS ASB2 mediates MLL degradation during hematopoietic differentiation. / Wang, Jingya; Muntean, Andrew G.; Hess, Jay.

In: Blood, Vol. 119, No. 5, 02.02.2012, p. 1151-1161.

Research output: Contribution to journalArticle

Wang, Jingya ; Muntean, Andrew G. ; Hess, Jay. / ECS ASB2 mediates MLL degradation during hematopoietic differentiation. In: Blood. 2012 ; Vol. 119, No. 5. pp. 1151-1161.
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