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    BIOMARKER:

    MLL fusion

    i
    Other names: HTRX1, HTRX, MLL1A, Mixed Lineage Leukemia 1, Myeloid/Lymphoid Or Mixed-Lineage Leukemia Protein 1, CXXC7, MLL1, TRX1, Zinc Finger Protein HRX, Trithorax-Like Protein, ALL-1, Lysine (K)-Specific Methyltransferase 2A, CXXC-Type Zinc Finger Protein 7, Histone-Lysine N-Methyltransferase 2A, Myeloid/Lymphoid Or Mixed-Lineage Leukemia, Lysine Methyltransferase 2A, MLL, Myeloid/Lymphoid Or Mixed-Lineage Leukemia, KMT2A
    11ms
    Menin Inhibitors: New Targeted Therapies for Specific Genetic Subtypes of Difficult-to-Treat Acute Leukemias. (PubMed, Cancers (Basel))
    MEN1 inhibitors (MIs), such as revumenib, ziftomenib, and other active small molecules, represent a promising new class of therapies currently under clinical development. It illustrates data from clinical trials and discusses the emergence of resistance mechanisms. In addition, we outline future directions for the use of MIs and emphasize the need for further research to fully realize the potential of these novel compounds, especially in the context of specific genetic subtypes of challenging AL.
    Review • Journal
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    NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEN1 (Menin 1)
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    KMT2A rearrangement • MLL rearrangement • MLL fusion
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    Revuforj (revumenib) • Komzifti (ziftomenib)
    12ms
    Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia. (PubMed, bioRxiv)
    Moreover, PF-9363 or genetic depletion of KAT7 can also overcome acquired genetic/non-genetic resistance to Menin inhibition. These data provide the molecular rationale for rapid clinical translation of combination therapy in MLL-FP leukaemia.
    Preclinical • Journal
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    KAT6A (Lysine Acetyltransferase 6A) • KAT6B (Lysine Acetyltransferase 6B)
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    MLL fusion
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    CTx-648
    12ms
    Synergistic Strategies for KMT2A-Rearranged Leukemias: Beyond Menin Inhibitor. (PubMed, Cancers (Basel))
    By integrating these diverse strategies, we propose a comprehensive therapeutic paradigm that targets multiple points of the leukemic transcriptional and epigenetic network. These combination approaches aim to disrupt key oncogenic pathways, reduce resistance, and enhance treatment efficacy, ultimately providing more durable remissions and improved survival for patients with KMT2A-rearranged leukemias.
    Review • Journal
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    KMT2A (Lysine Methyltransferase 2A) • BRD4 (Bromodomain Containing 4) • DOT1L (DOT1 Like Histone Lysine Methyltransferase)
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    MLL rearrangement • MLL fusion
    1year
    Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia. (PubMed, J Med Chem)
    Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50 (MOLM-13): 1.25 ± 0.18 μM; CC50 (MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.
    Journal
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    KMT2A (Lysine Methyltransferase 2A)
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    MLL rearrangement • MLL rearrangement • MLL fusion
    1year
    A RUNX1: RUNX1T1 AML with a simultaneous false positive KMT2A rearrangement: FISH interpretation pitfalls. (PubMed, Hematology)
    Given that KMT2A FISH probes cover approximately 1 Mb around KMT2A, this subtle shift led to a split-apart signal pattern mimicking a genuine KMT2A rearrangement, resulting in a false positive FISH interpretation. This case highlights a false positive KMT2Ar in primary AML, indicating the need for additional molecular testing for confirmation.
    Journal
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    RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1)
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    KMT2A rearrangement • MLL rearrangement • RUNX1-RUNX1T1 fusion • MLL fusion
    1year
    Capturing Fusion in Hematological Malignancies through Targeted RNASeq (AMP 2024)
    We have demonstrated the capability of the SureSeq Myeloid Fusion Complete NGS Workflow Solution to detect known rearrangements in AML. We observed 100% concordance with qPCR and FISH for all samples tested. The NGS data permitted single-exon resolution of breakpoints and revealed the presence of multiple breakpoints which would have remained undetected with FISH.
    ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • AFF1 (AF4/FMR2 Family Member 1) • PML (Promyelocytic Leukemia) • MECOM (MDS1 And EVI1 Complex Locus) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • AFDN (Afadin, Adherens Junction Formation Factor) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor)
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    BCR-ABL1 fusion • MLL fusion
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    SureSeq™ Myeloid Fusion Panel
    1year
    Design and development of a series of 4-(piperazin-1-yl)pyrimidines as irreversible menin inhibitors. (PubMed, Eur J Med Chem)
    This effect of 37 is not involved in proteasomal degradation, and may directly affect the synthesis of menin protein, which offers a significant advantage in addressing acquired resistance to menin inhibitors. Further study showed that compound 37 has prolonged anti-leukemic action and exhibits promising in vivo efficacy, making it a valuable probe for further menin-MLL interaction studies.
    Journal
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    NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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    NPM1 mutation • MLL rearrangement • MLL rearrangement • MLL fusion
    1year
    Unraveling MLL1-fusion Leukemia: Epigenetic Revelations from an iPS Cell Point Mutation. (PubMed, J Biol Chem)
    Challenging existing models, our findings imply that MLL1F-induced leukemias arise from a dominant-negative impact on MLL1's histone methyltransferase activity. We propose targeting SETd1a in precision medicine as a new therapeutic approach for MLL1-associated leukemias.
    Journal
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    HOXA9 (Homeobox A9) • MEIS1 (Meis Homeobox 1) • SNAI2 (Snail Family Transcriptional Repressor 2) • ZEB1 (Zinc Finger E-box Binding Homeobox 1) • HOTTIP (HOXA Distal Transcript Antisense RNA) • SETD1A (SET Domain Containing 1A)
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    MLL mutation • MLL fusion
    over1year
    Structural studies of intrinsically disordered MLL-fusion protein AF9 in complex with peptidomimetic inhibitors. (PubMed, Protein Sci)
    We show that the overall complex structures closely resemble the reported NMR structure of AF9 AHD/DOT1L with notable difference in the conformation of the β-hairpin region, stabilized through conserved hydrogen bonds network. These first series of AF9 AHD/peptidomimetics complex structures are providing insights of the protein-inhibitor interactions and will facilitate further development of novel inhibitors targeting the AF9/ENL AHD domain.
    Journal
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    DOT1L (DOT1 Like Histone Lysine Methyltransferase) • MLLT3 (MLLT3 Super Elongation Complex Subunit)
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    MLL rearrangement • MLL fusion
    over1year
    The Menin story in acute myeloid leukaemia-The road to success. (PubMed, Br J Haematol)
    Other HOX and MEIS1 expressing leukaemias may also be sensitive to Menin inhibition. Following the encouraging results as monotherapy in refractory and relapsed AML, the combination of Menin inhibitors with chemotherapeutic agents and other targeted drugs is being investigated clinically.
    Review • Journal
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    NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1) • PBX3 (PBX Homeobox 3)
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    NPM1 mutation • MLL rearrangement • MLL mutation • MLL fusion
    over1year
    Optimized Cytogenetic Risk-Group Stratification of KMT2A-Rearranged Pediatric Acute Myeloid Leukemia. (PubMed, Blood Adv)
    We provide evidence to incorporate the five adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcome, and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.
    Journal
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    KMT2A (Lysine Methyltransferase 2A) • AFF1 (AF4/FMR2 Family Member 1) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • SEPTIN6 (Septin 6) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor)
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    MLL rearrangement • MLL fusion
    over1year
    Bahcc1 is critical for the aberrant epigenetic program in a mouse model of MLL-ENL-mediated leukemia. (PubMed, Blood Adv)
    In a public database, high BAHCC1 expression was associated with a poor prognosis in pediatric AML, in which BAHCC1 expression was significantly lower in MLL-AF9-AML than in other MLL-fusion-AML. These findings shed light on the distinct immortalization potential of HSPCs and suggest a novel MLL-fusion-Bahcc1 axis, which may lead to development of molecular targeted therapy against MLL-fusion-mediated leukemia.
    Preclinical • Journal
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    CD48 (CD48 Molecule) • CDKN1C (Cyclin Dependent Kinase Inhibitor 1C)
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    MLL rearrangement • MLL fusion