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Gene | KMT2A AFF1 |
Variant | KMT2A - AFF1 |
Impact List | fusion |
Protein Effect | gain of function |
Gene Variant Descriptions | KMT2A-AFF1 (also referred to as MLL-AF4) results from the fusion of KMT2A and AFF1, resulting in repression of CDKN1B transcription, which eventually leads to leukemogenesis (PMID: 20194896, PMID: 16169901). |
Associated Drug Resistance |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
KMT2A - AFF1 | acute lymphoblastic leukemia | sensitive | I-BET151 | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, treatment with I-BET151 in acute lymphoblastic leukemia cell lines harboring a KMT2A-AFF1 fusion resulted in growth inhibition, cell cycle arrest, increased apoptosis, and down-regulation of BRD4 targets CDK6, c-MYC, and BCL2 in culture, and resulted in reduced leukemic engraftment and decreased disease burden in a patient-derived xenograft (PDX) model and prolonged survival and reduced cellularity in a cell line xenograft model (PMID: 29748211). | 29748211 |
KMT2A - AFF1 | B-cell acute lymphoblastic leukemia | predicted - resistant | Blinatumomab | Case Reports/Case Series | Actionable | In a clinical case study, Blincyto (blinatumomab) treatment in a patient with B-lymphoblastic leukemia harboring KMT2A-AFF1 resulted in lineage switch as demonstrated by identification of myeloid sarcoma of the breast and acute myeloid leukemia within one month of treatment onset, along with mixed phenotype acute leukemia observed following cessation of treatment (PMID: 31885955). | 31885955 |
KMT2A - AFF1 | acute myeloid leukemia | predicted - sensitive | AZD5153 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, AZD5153 inhibited proliferation of acute myeloid leukemia cells harboring KMT2A-AFF1 (MLL-AF4) in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27573426). | 27573426 |
KMT2A - AFF1 | leukemia | sensitive | I-BET151 + SGC0946 | Preclinical - Cell culture | Actionable | In a preclinical study, I-BET151 and SGC0946 synergistically inhibited proliferation of leukemia cells harboring KMT2A-AFF1 in culture (PMID: 27294782). | 27294782 |
KMT2A - AFF1 | acute lymphoblastic leukemia | predicted - sensitive | AZD5153 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, AZD5153 inhibited proliferation of acute lymphocytic leukemia cells harboring KMT2A-AFF1 (MLL-AF4) in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27573426). | 27573426 |
KMT2A - AFF1 | acute lymphoblastic leukemia | predicted - sensitive | I-BET151 + Prednisolone | Preclinical - Cell culture | Actionable | In a preclinical study, treatment with I-BET151 enhanced the efficacy of Omnipred (prednisolone) in acute lymphoblastic leukemia cells harboring a KMT2A-AFF1 (also known as MLL-AF4) fusion, resulting in increased cell death compared to either therapy alone in culture (PMID: 29748211). | 29748211 |
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 |
KMT2A - AFF1 | acute myeloid leukemia | predicted - sensitive | Decitabine + Tretinoin | Preclinical - Cell culture | Actionable | In a preclinical study, combination treatment of Tretinoin and Dacogen (decitabine) resulted in growth inhibition in acute myeloid leukemia cells harboring a KMT2A-AFF1 fusion in cell culture (PMID: 23063977). | 23063977 |
KMT2A - AFF1 | acute myeloid leukemia | sensitive | MI-503 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, MI-503 reduced expression of KMT2A (MLL) fusion target genes, inhibited growth of an acute myeloid leukemia (AML) cell lines harboring KMT2A-AFF1 (MLL-AF4) in culture, and inhibited tumor growth and progression in an AML cell line xenograft model harboring KMT2A-AFF1 (MLL-AF4) (PMID: 25817203). | 25817203 |
KMT2A - AFF1 | acute myeloid leukemia | predicted - sensitive | Tranylcypromine + Tretinoin | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Parnate (tranylcypromine) resulted in increased sensitivity to Tretinoin treatment in acute myeloid leukemia cells harboring a KMT2A-AFF1 fusion (also known as MLL-AF4), with inhibition of cell growth and CD11b expression in culture (Blood (2012) 120 (21): 1345.). | detail... |
KMT2A - AFF1 | acute lymphoblastic leukemia | predicted - sensitive | I-BET151 + Panobinostat | Preclinical - Cell line xenograft | Actionable | In a preclinical study, acute lymphoblastic leukemia cell line xenograft models harboring a KMT2A-AFF1 fusion treated with a combination therapy of I-BET151 and Farydak (panobinostat) demonstrated reduced cellularity and a prolonged survival of 34 days compared to 28 days for mice receiving either I-BET151 alone or 21 days for those treated with control (PMID: 29748211). | 29748211 |
KMT2A - AFF1 | acute myeloid leukemia | sensitive | Dinaciclib | Preclinical | Actionable | In a preclinical study, treatment with Dinaciclib resulted in induced cell death of acute myeloid leukemia cells harboring KMT2A-AFF1 in culture (PMID: 26627013). | 26627013 |
KMT2A - AFF1 | acute lymphoblastic leukemia | predicted - sensitive | Givinostat + I-BET151 | Preclinical - Cell culture | Actionable | In a preclinical study, combination therapy of I-BET151 and Givinostat (ITF2357) in acute lymphoblastic leukemia cell lines harboring a KMT2A-AFF1 fusion resulted in either a synergistic or additive effect, demonstrating increased apoptosis compared to either therapy alone in cell culture (PMID: 29748211). | 29748211 |
KMT2A - AFF1 FLT3 exon 14 ins | acute myeloid leukemia | predicted - sensitive | CYC065 | Preclinical - Cell culture | Actionable | In a preclinical study, an acute myeloid leukemia cell line harboring KMT2A-AFF1 and a FLT3-ITD was sensitive to treatment with CYC065 (Fadraciclib) in culture, demonstrating decreased cell viability (PMID: 32645016). | 32645016 |
Molecular Profile | Protein Effect | Treatment Approaches |
---|---|---|
KMT2A - AFF1 | gain of function | |
KMT2A - AFF1 FLT3 exon 14 ins | ||
KMT2A - AFF1 FLT3 mut |