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Ref Type Journal Article
PMID (28065413)
Authors Liang K, Volk AG, Haug JS, Marshall SA, Woodfin AR, Bartom ET, Gilmore JM, Florens L, Washburn MP, Sullivan KD, Espinosa JM, Cannova J, Zhang J, Smith ER, Crispino JD, Shilatifard A
Title Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia.
Journal Cell
Vol
Issue
Date 2017 Jan 02
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
IRAK1/4 IRAK1/4 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
IRAK1/4 IRAK1/4 Inhibitor 1 IRAK1/4 is an inhibitor of interleukin-1 receptor associated kinases 1 and 4, which results in stabilization of wild-type KMT2A, thereby potentially leading to inhibition of cell growth and delayed disease progression in KMT2A fusion specific cancers (PMID: 28065413).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KMT2A - MLLT3 leukemia sensitive IRAK1/4 Preclinical Actionable In a preclinical study, a transgenic leukemic mouse model harboring KMT2A-MLLT3 demonstrated sensitivity to IRAK1/4, resulting in delayed progression and improved survival (PMID: 28065413). 28065413
KMT2A - AFF1 leukemia sensitive IRAK1/4 Preclinical - Cell culture Actionable In a preclinical study, leukemia cells harboring KMT2A-AFF1 demonstrated sensitivity to IRAK1/4 in culture, resulting in decreased cell proliferation (PMID: 28065413). 28065413