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|Ref Type||Journal Article|
|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.|
|Date||2017 Jan 02|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|