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    BIOMARKER:

    MLL rearrangement

    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
    2d
    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
    |
    NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEN1 (Menin 1)
    |
    KMT2A rearrangement • MLL rearrangement • MLL fusion
    |
    Revuforj (revumenib) • ziftomenib (KO-539)
    2d
    A Distinct Alternative mRNA Splicing Profile Identifies the Oncogenic CD44 Transcript Variant 3 in KMT2A-Rearranged Pediatric T-cell Acute Lymphoblastic Leukemia Cells. (PubMed, Exp Hematol)
    Lastly, increased levels of activating methylation in the promoter region of CD44 were identified followed by an upregulation of the oncogenic transcript variant CD44v3 in KMT2A-r T-ALL. Together this suggests that CD44v3 could play a potential role as gene expression-based risk stratification of KMT2A-r rearranged T-ALL and could possibly serve as a therapeutic target using splicing modulators.
    Journal • IO biomarker
    |
    BCL2 (B-cell CLL/lymphoma 2) • KMT2A (Lysine Methyltransferase 2A) • ESRP1 (Epithelial Splicing Regulatory Protein 1)
    |
    MLL rearrangement
    2d
    Molecular measurable residual disease before transplantation independently predicts survival and relapse risk in adult lysine methyltransferase 2a-rearranged acute myeloid leukemia. (PubMed, Cancer)
    Residual KMT2A-r before allo-HSCT independently predicts the risk of survival and relapse, and donor lymphocyte infusion or posttransplantation maintenance therapies should be considered for patients who have AML with detectable molecular MRD.
    Journal
    |
    KMT2A (Lysine Methyltransferase 2A)
    |
    MLL rearrangement • MLL translocation
    2d
    Lactylation modulation identifies key biomarkers and therapeutic targets in KMT2A-rearranged AML. (PubMed, Sci Rep)
    The study also suggested PI3K inhibitors and Pevonedistat as possible therapeutic options to modulate immune cell infiltration. Our findings confirm the critical role of lactylation in KMT2Ar-AML and identify six key genes that may serve as biomarkers for diagnosis and treatment. In addition to highlighting the need for further validation in clinical settings, these findings contribute to our understanding of KMT2Ar-AML's molecular mechanisms.
    Journal
    |
    LDHB (L-lactate dehydrogenase B chain) • KMT2A (Lysine Methyltransferase 2A) • PRDX1 (Peroxiredoxin 1) • LGALS1 (Galectin 1) • S100A6 (S100 calcium binding protein A6)
    |
    KMT2A rearrangement • MLL rearrangement
    |
    pevonedistat (MLN4924)
    2d
    Prediction model establishment of prognosis factors for acute myeloid leukemia based on the SEER database. (PubMed, Sci Rep)
    Patients were classified into high-risk and low-risk groups based on nomogram scores, with significant differences in OS and CSS between these groups (P < 0.001). This study developed innovative nomograms that combine clinical and treatment factors to predict 1-, 3-, and 5-year survival rates for patients with t (9;11) (p22; q23) AML.
    Journal
    |
    KMT2A (Lysine Methyltransferase 2A)
    |
    KMT2A rearrangement • MLL rearrangement
    10d
    Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Leukemia (clinicaltrials.gov)
    P1, N=24, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025
    Trial completion date • Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1)
    |
    MLL rearrangement
    |
    cyclophosphamide • fludarabine IV
    10d
    90Y-DOTA-anti-CD25 Basiliximab, Fludarabine, Melphalan, and Total Marrow and Lymphoid Irradiation for the Treatment of High-Risk Acute Leukemia or Myelodysplastic Syndrome (clinicaltrials.gov)
    P1, N=12, Recruiting, City of Hope Medical Center | Trial completion date: Dec 2024 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Jun 2027
    Trial completion date • Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • IL2RA (Interleukin 2 receptor, alpha) • ISG20 (Interferon Stimulated Exonuclease Gene 20)
    |
    MLL rearrangement • IL2RA expression
    |
    melphalan • fludarabine IV • Kepivance (palifermin) • Simulect (basiliximab)
    12d
    The Factors Related to Treatment Failure in Children with Acute Lymphoblastic leukemia--Analysis of Multi-Center Data from Real World in Fujian Province (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi)
    The treatment failure of children with ALL in our province is still relatively high, with relapse being the main cause of treatment failure, while treatment related death and treatment abandonment caused by economic factors are the main causes of non-relapse related death.
    Retrospective data • Journal • Real-world evidence
    |
    ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • KMT2A (Lysine Methyltransferase 2A)
    |
    KMT2A rearrangement • MLL rearrangement
    14d
    Intensified conditioning containing decitabine versus standard myeloablative conditioning for adult patients with KMT2A-rearranged leukemia: a multicenter retrospective study. (PubMed, BMC Med)
    These results suggest that intensified conditioning containing Dec might be a better strategy than standard myeloablative conditioning for adult patients with KMT2A-r leukemia undergoing allo-HSCT.
    Retrospective data • Journal
    |
    KMT2A (Lysine Methyltransferase 2A)
    |
    MLL rearrangement
    |
    cyclophosphamide • decitabine • busulfan
    18d
    AALL15P1: Azacitidine and Combination Chemotherapy in Treating Infants With Acute Lymphoblastic Leukemia and KMT2A Gene Rearrangement (clinicaltrials.gov)
    P2, N=78, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Nov 2025
    Trial completion date
    |
    KMT2A (Lysine Methyltransferase 2A)
    |
    KMT2A rearrangement • MLL rearrangement
    |
    cytarabine • azacitidine • cyclophosphamide • methotrexate • vincristine • daunorubicin • leucovorin calcium • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine • Hemady (dexamethasone tablets) • Starasid (cytarabine ocfosfate)
    21d
    Menin inhibitors in the treatment of acute myeloid leukemia. (PubMed, Blood)
    Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML such as KMT2A rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.
    Journal
    |
    NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
    |
    NPM1 mutation • KMT2A rearrangement • MLL rearrangement
    22d
    The Significance of Detecting an Unusual Myeloblast Immunophenotype in a Presumptive Clinical Diagnosis of Myelodysplastic Syndromes. (PubMed, Arch Pathol Lab Med)
    Of the remaining 10 cases, 4 uncharacteristically had no detectable molecular genetic abnormalities. Our data show that, if a presumptive MDS shows a nonprimitive blast phenotype, caution is needed to rule out AML with recurrent genetic abnormality with an oligoblastic presentation, high-risk myeloid neoplasms with double-hit TP53 mutation with abnormal erythroid proliferation, and MDS with molecular-genetic and clinical features more akin to AML.
    Journal
    |
    TP53 (Tumor protein P53) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • CD33 (CD33 Molecule) • CD34 (CD34 molecule) • ANPEP (Alanyl Aminopeptidase, Membrane)
    |
    TP53 mutation • NPM1 mutation • MLL rearrangement
    22d
    Bone-Marrow-Targeted Nanocomposite Abrogates C-Myb-Survivin Cross Talk in MLL-AF9-Rearranged Acute Myeloid Leukemia in In Vitro and In Vivo Patient-Derived Xenograft Models. (PubMed, ACS Appl Mater Interfaces)
    IBD functionalization enhanced the downregulation of C-Myb and C-Myb-Survivin cross talk in bone marrow and spleen tissue responsible for AML onset, maintenance, and pathogenesis. Further C-Myb binding to Survivin promoter was abrogated by the present bone-marrow-targeted nanotherapy, signifying its translational potential for AML therapeutics.
    Preclinical • Journal
    |
    KIT (KIT proto-oncogene, receptor tyrosine kinase) • BIRC5 (Baculoviral IAP repeat containing 5) • ITGAM (Integrin, alpha M)
    |
    MLL rearrangement
    24d
    WD repeat domain 5 (WDR5) inhibitors: a patent review (2016-present). (PubMed, Expert Opin Ther Pat)
    Our survey illuminates challenges for the field to overcome: a broad lack of chemical diversity, confusion about the molecular mechanism of WIN-site inhibitors, a paucity of brain-penetrant scaffolds despite emerging evidence of activity in brain cancers, sparse pharmacokinetic, metabolic, and disposition characterization, and the absence of safety or efficacy data in humans. It is our opinion that the best-in-class WIN-site inhibitors (from the imidazole class) merit advancement into clinical testing, likely against leukemia, which should provide much-needed clarity about the exciting but unproven potential of WDR5 as a next-generation therapeutic target.
    Review • Journal
    |
    WDR5 (WD Repeat Domain 5)
    |
    MLL rearrangement
    26d
    Protocol for CRISPR-Cas9-mediated induction of KMT2A rearrangements in cell line and umbilical cord blood hematopoietic stem and progenitor cells. (PubMed, STAR Protoc)
    We describe steps for patient-specific single guide RNA (sgRNA) design, optimized sgRNA in vitro transcription, detailed purification of hematopoietic stem and progenitor cells (HSPCs) from umbilical cord blood (UCB), and CRISPR-Cas9 editing of the test cell line K562 as well as UCB HSPCs. The provided methodology is donor independent.
    Preclinical • Journal
    |
    KMT2A (Lysine Methyltransferase 2A)
    |
    KMT2A rearrangement • MLL rearrangement
    27d
    Only Infant MLL-Rearranged Leukemia Is Susceptible to an Inhibition of Polo-like Kinase 1 (PLK-1) by Volasertib. (PubMed, Int J Mol Sci)
    Importantly, the poor response could be overcome by a combinatorial strategy with alisertib, an Aurora kinase A inhibitor. Our study emphasizes the importance of considering the cell of origin in therapeutic decision-making and provides the rationale for evaluating volasertib and alisertib in MLLr leukemia.
    Journal
    |
    CD34 (CD34 molecule) • AURKA (Aurora kinase A) • PLK1 (Polo Like Kinase 1)
    |
    MLL rearrangement
    |
    volasertib (NBL-001) • alisertib (MLN8237)
    28d
    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
    |
    KMT2A (Lysine Methyltransferase 2A) • BRD4 (Bromodomain Containing 4) • DOT1L (DOT1 Like Histone Lysine Methyltransferase)
    |
    MLL rearrangement • MLL fusion
    28d
    Patient-Specific Circulating Tumor DNA for Monitoring Response to Menin Inhibitor Treatment in Preclinical Models of Infant Leukemia. (PubMed, Cancers (Basel))
    Notably, ctDNA analysis proved to be a superior predictor of MRD compared to PB assessment alone, especially in instances of low disease burden. These findings highlight the potential of ctDNA as a sensitive biomarker for monitoring treatment response and detecting MRD in infant MLL-r ALL.
    Preclinical • Journal • Circulating tumor DNA
    |
    KMT2A (Lysine Methyltransferase 2A)
    |
    MLL rearrangement
    1m
    BMT-06: Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) (clinicaltrials.gov)
    P2, N=27, Recruiting, University of Illinois at Chicago | Trial completion date: Nov 2024 --> Dec 2026 | Trial primary completion date: Nov 2024 --> Dec 2026
    Trial completion date • Trial primary completion date • Post-transplantation
    |
    RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-DQB1 (Major Histocompatibility Complex, Class II, DQ Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B)
    |
    RUNX1 mutation • ASXL1 mutation • MLL rearrangement • MLL rearrangement • MLL translocation
    |
    cyclophosphamide • fludarabine IV
    1m
    Comprehensive Genomic Profiling (CGP) of Acute Myeloid Leukemias with Foundation One Heme Identifies Actionable Genomic Alterations and Biomarkers (ASH 2024)
    Current best practices for the diagnosis, classification, prognostication, and treatment of AML call for the assessment of the presence and absence of numerous genomic alterations. Therefore, in contrast to single-gene or small-panel molecular testing, the F1H platform can simplify such assessment via a CGP approach.
    IO biomarker
    |
    TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • BCL2 (B-cell CLL/lymphoma 2) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • SRSF2 (Serine and arginine rich splicing factor 2) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • BCOR (BCL6 Corepressor) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • NUP214 (Nucleoporin 214) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • MRTFA (Myocardin Related Transcription Factor A) • RBM15 (RNA Binding Motif Protein 15)
    |
    TP53 mutation • NPM1 mutation • KMT2A rearrangement • MLL rearrangement • U2AF1 mutation • CEBPA mutation • MLL mutation • NPM1 W288
    |
    FoundationOne® Heme CDx
    1m
    YAP1::KMT2A-rearranged sarcomas harbor a unique methylation profile and are distinct from sclerosing epithelioid fibrosarcoma and low-grade fibromyxoid sarcoma. (PubMed, Virchows Arch)
    DNA methylation analysis further showed that YAP1::KMT2A-rearranged sarcomas formed a distinct cluster, which was clearly separate from both conventional SEF and low-grade fibromyxoid sarcoma (LGFMS). These results suggest that YAP1::KMT2A-rearranged sarcomas likely represent a unique sarcoma subtype with propensity for aggressive behavior.
    Journal
    |
    KMT2A (Lysine Methyltransferase 2A) • EWSR1 (EWS RNA Binding Protein 1) • YAP1 (Yes associated protein 1) • FUS (FUS RNA Binding Protein) • MUC4 (Mucin 4, Cell Surface Associated) • CREB3L1 (CAMP Responsive Element Binding Protein 3 Like 1)
    |
    MLL rearrangement • MUC4 expression
    1m
    HMX3 is a critical vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia. (PubMed, Leukemia)
    Strikingly, HMX3 silencing in KMT2A::MLLT3 patient cells resulted in cell cycle arrest, monocytic differentiation and apoptosis. Thus, the neuronal transcription factor HMX3 is a leukemia-specific vulnerability in KMT2A::MLLT3 AML.
    Journal
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • KMT2A (Lysine Methyltransferase 2A) • CREBBP (CREB binding protein) • CD34 (CD34 molecule) • MECOM (MDS1 And EVI1 Complex Locus) • KAT6A (Lysine Acetyltransferase 6A) • MLLT3 (MLLT3 Super Elongation Complex Subunit)
    |
    MLL rearrangement
    2ms
    Targeting chromatin modifying complexes in acute myeloid leukemia. (PubMed, Stem Cells Transl Med)
    This review explores recent discoveries of how leukemic cells hijack these complexes and their interactions with other chromatin regulators to promote disease progression. We also discuss inhibitors targeting these complexes that have demonstrated therapeutic efficacy in preclinical and clinical studies and propose novel therapeutic combinations targeting the KMT2A and PRC1/2 broader interacting networks to overcome issues of resistance to existing monotherapies.
    Journal
    |
    NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1)
    |
    NPM1 mutation • MLL rearrangement
    2ms
    BRAF V600E-Mutant Acute Myeloid Leukemia: A Case Series and Literature Review of a Rare Entity. (PubMed, Genes (Basel))
    Although it is uncertain whether the complex karyotype and somatic mutations observed in case 1 and KMT2A rearrangement and variants identified in case 2 may have either independently or cooperatively conferred a poor prognosis, we contend that additional comprehensive studies are needed to further understand the pathophysiology and prognosis of BRAF mutations in AML. We further posit whether patients with BRAF V600E-mutant AML may benefit from the combined use of BRAF inhibitors and/or RAS-pathway-targeting regimens, which are currently FDA-approved for the treatment of BRAF V600-mutant solid tumors and BRAF-mutant histiocytic neoplasms.
    Review • Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)
    |
    BRAF V600E • BRAF V600 • TET2 mutation • KMT2A rearrangement • KRAS G12A • KRAS G12 • MLL rearrangement • MLL rearrangement
    2ms
    AUGMENT-101: A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation (clinicaltrials.gov)
    P1/2, N=413, Recruiting, Syndax Pharmaceuticals | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2027
    Trial completion date • Trial primary completion date
    |
    KMT2A (Lysine Methyltransferase 2A) • NUP98 (Nucleoporin 98 And 96 Precursor 2)
    |
    NPM1 mutation • MLL rearrangement • MLL rearrangement • NUP98 rearrangement
    |
    Revuforj (revumenib) • Tybost (cobicistat)
    2ms
    Menin inhibitors for the treatment of acute myeloid leukemia: challenges and opportunities ahead. (PubMed, J Hematol Oncol)
    More importantly, approval of the combination of the BCl-2 inhibitor, venetoclax, and hypomethylating agents or low dose cytarabine provided unprecedented breakthrough for the frontline treatment of older, unfit AML patients. Recent development of menin inhibitors targeting AML with KMT2A rearrangements or NPM1 mutations could represent a promising new horizon of treatment for patients within these subsets of AML. Our current review will focus on a summary and updates of recent developments of menin inhibitors in the treatment of AML, on the challenges ahead arising from drug resistance, as well as on the opportunities of novel combinations with menin inhibitors.
    Review • Journal • IO biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
    |
    NPM1 mutation • KMT2A rearrangement • MLL rearrangement
    |
    Venclexta (venetoclax) • cytarabine
    2ms
    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
    |
    KMT2A (Lysine Methyltransferase 2A)
    |
    MLL rearrangement • MLL rearrangement • MLL fusion
    2ms
    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
    |
    RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1)
    |
    KMT2A rearrangement • MLL rearrangement • RUNX1-RUNX1T1 fusion • MLL fusion
    2ms
    AALL1131: Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations (clinicaltrials.gov)
    P3, N=5949, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025
    Trial completion date
    |
    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)
    |
    MLL rearrangement • MLL rearrangement
    |
    dasatinib • cytarabine • doxorubicin hydrochloride • cyclophosphamide • etoposide IV • methotrexate • vincristine • daunorubicin • clofarabine • leucovorin calcium • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine • Hemady (dexamethasone tablets) • Starasid (cytarabine ocfosfate)
    2ms
    Evaluation of OGT's SureSeq Myeloid Fusion Complete NGS Workflow Solution V2 for Partner-Agnostic Fusion Gene Detection in Acute Leukemias (AMP 2024)
    We demonstrated the capability of OGT's SureSeq Myeloid Fusion Complete NGS Workflow Solution V2 to achieve 100% accurate detection for novel and canonical translocations. By allowing concurrent detection of multiple known and novel rearrangements, NGS assays offer an economical and efficient alternative to routine cytogenetic approaches.
    Next-generation sequencing
    |
    ABL1 (ABL proto-oncogene 1) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • MECOM (MDS1 And EVI1 Complex Locus) • HOXD8 (Homeobox D8)
    |
    KMT2A rearrangement • MLL rearrangement
    |
    SureSeq™ Myeloid Fusion Panel
    2ms
    Lineage Switch from Therapy-Related B Cell Acute Lymphoblastic Leukemia to Pure Erythroid Leukemia Following CD20-Directed Immunotherapy: A Mechanism for Immune Escape? (AMP 2024)
    Six weeks later, while receiving the CD20-directed immunotherapies glofitamab and obinutuzumab, another bone marrow biopsy revealed eradication of the B-ALL and new involvement by pure erythroid leukemia (PEL). This patient's B-ALL lacked an IGH::BCL2 fusion resulting from t(14; 18), suggesting it did not arise through transformation of his prior FL/DLBCL. Instead, the B-ALL was likely caused by his extensive exposure to genotoxic chemotherapy drugs – including alkylating agents – for his preceding lymphomas. The shared cytogenetic and molecular features between this patient's B-ALL and PEL imply they are clonally related.
    IO biomarker
    |
    TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • CD20 (Membrane Spanning 4-Domains A1) • KMT2A (Lysine Methyltransferase 2A)
    |
    TP53 mutation • KMT2A rearrangement • MLL rearrangement • BCL2 fusion
    |
    TruSight Myeloid Sequencing Panel
    |
    Gazyva (obinutuzumab) • Columvi (glofitamab-gxbm)
    2ms
    KMT2A (MLL1) Rearrangements in Hematolymphoid Malignancies: A Genomic Landscape Study (ASH 2024)
    Conclusions : Rearrangements in the KMT2A gene in AML are common and may emerge as a new target of therapy for AML patients. This genomic landscape study reveals significant differences in import GA associated with AML in KMT2Ara and KMT2Anra cases.
    Tumor mutational burden
    |
    KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • WT1 (WT1 Transcription Factor)
    |
    KRAS G12C • KMT2A rearrangement • KRAS G12 • MLL rearrangement • MLL rearrangement • MLL mutation
    |
    FoundationOne® Heme CDx
    2ms
    Umbilical Cord Blood Transplantation Using a Myeloablative Preparative Regimen for Hematological Diseases (clinicaltrials.gov)
    P=N/A, N=200, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025
    Trial completion date • Trial primary completion date
    |
    KMT2A (Lysine Methyltransferase 2A) • IKZF1 (IKAROS Family Zinc Finger 1)
    |
    MLL rearrangement • MLL rearrangement
    |
    cyclophosphamide • fludarabine IV • cyclosporin A microemulsion
    2ms
    A dual role for PSIP1/LEDGF in T cell acute lymphoblastic leukemia. (PubMed, Sci Adv)
    In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.
    Journal
    |
    KMT2A (Lysine Methyltransferase 2A)
    |
    MLL rearrangement
    2ms
    Chidamide Combined with (+) -JQ-1 to Kill MLL-Rearrangement Acute Myeloid Leukemia Cells by Disrupting the DNA Damage Response Pathway (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi)
    Chidamide combined with (+)-JQ-1 can inhibit the proliferation of MLL-r AML cells, inhibit the initiation of protective self-repair of these leukemia cells by inhibiting the DNA damage response pathway, and ultimately increase the apoptosis of these cells, but non- MLL-r AML cells have no similar results.
    Journal • IO biomarker
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    BCL2 (B-cell CLL/lymphoma 2) • KMT2A (Lysine Methyltransferase 2A) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • CHEK1 (Checkpoint kinase 1) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • BRD4 (Bromodomain Containing 4) • TP53BP1 (Tumor Protein P53 Binding Protein 1)
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    MLL rearrangement • MLL rearrangement • BCL2 expression • BAX expression
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    JQ-1 • Epidaza (chidamide)
    3ms
    CRLF2-rearranged B-cell ALL with extramedullary lineage switch to AML following CD19-targeted therapy. (PubMed, J Immunother Cancer)
    To our knowledge, these are the first cases of LS to be reported in patients with CRLF2 rearranged acute lymphoblastic leukemia. In addition to raising awareness that this genetic mutation may associate with lineage plasticity, our cases illustrate the importance of multi-modal disease surveillance in the diagnosis of LS.
    Journal
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    KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2)
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    KMT2A rearrangement • MLL rearrangement • CRLF2 rearrangement
    3ms
    Rational fragment-based design of compounds targeting the PWWP domain of the HRP family. (PubMed, Eur J Med Chem)
    Given that the affinity of H3K36me2/3 nucleosomes to LEDGF/p75 is driven by interactions within the pocket as well as with the DNA-binding residues, we suggest that future compound development should target the latter region as well. Beyond drug discovery, our compounds can be employed to devise tool compounds to investigate the mechanism of LEDGF/p75 in epigenetic regulation.
    Journal
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    NSD3 (Nuclear Receptor Binding SET Domain Protein 3) • NSD2 (Nuclear Receptor Binding SET Domain Protein 2)
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    MLL rearrangement
    3ms
    Exploring the contribution of Zfp521/ZNF521 on primary hematopoietic stem/progenitor cells and leukemia progression. (PubMed, Cell Tissue Res)
    This review provides an overview of the regulatory network involving ZNF521, which plays a crucial role in controlling both HSC self-renewal and differentiation pathways. Furthermore, we examine the impact of ZNF521 on the leukemic phenotype and consider it a potential marker for MLL-AF9+ AML.
    Review • Journal
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    ZNF501 (Zinc Finger Protein 501)
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    MLL rearrangement • Chr t(9;11)
    3ms
    Recent Developments and Evolving Therapeutic Strategies in KMT2A-Rearranged Acute Leukemia. (PubMed, Cancer Med)
    Studies indicate that KMT2A rearrangements are present in over 70% of infant leukemia cases, approximately 10% of adult AML cases, and numerous instances of secondary acute leukemias, making it a disease of critical concern to clinicians and researchers alike. The future of KMT2A-r acute leukemia research is characterized by an expanding knowledge of the disease's biology, with an emphasis on personalized therapies, immunotherapies, genomic advancements, and innovative therapeutic combinations. The overarching aim is to enhance patient outcomes, lessen the disease burden, and elevate the quality of life for those affected. Ongoing research and clinical trials in this area continue to offer promising opportunities for refining treatment strategies and improving patient prognosis.
    Review • Journal
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    KMT2A (Lysine Methyltransferase 2A)
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    KMT2A rearrangement • MLL rearrangement
    3ms
    The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency. (PubMed, J Hematol Oncol)
    Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.
    Journal
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    KMT2A (Lysine Methyltransferase 2A) • KAT6A (Lysine Acetyltransferase 6A) • MLLT3 (MLLT3 Super Elongation Complex Subunit)
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    MLL rearrangement
    3ms
    Clinical features and long-term outcomes of pediatric patients with de novo acute myeloid leukemia in China with or without specific gene abnormalities: a cohort study of patients treated with BCH-AML 2005. (PubMed, Hematology)
    Not achieving complete remission after induction 2 was found to be an independent prognostic factor for OS and EFS. These findings indicate that genetic abnormalities could be considered stratification factors, predict patient outcomes, and imply the application of targeted therapy.
    Journal
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    FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • NUP214 (Nucleoporin 214) • CBFB (Core-Binding Factor Subunit Beta 2) • DEK (DEK Proto-Oncogene)
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    FLT3-ITD mutation • KIT mutation • KMT2A rearrangement • MLL rearrangement • DEK-NUP214 rearrangement
    3ms
    A simplified and robust risk stratification model for stem cell transplantation in pediatric acute myeloid leukemia. (PubMed, Cell Rep Med)
    Moreover, by incorporating the FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) allelic ratio, the pAML SCT model is refined, enhancing its ability to effectively select suitable candidates. We develop a simple and robust risk stratification model for pAML patients undergoing SCT, to aid in risk stratification and inform pretransplant decision-making at CR1 stage.
    Journal
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    FLT3 (Fms-related tyrosine kinase 3) • KMT2A (Lysine Methyltransferase 2A)
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    KMT2A rearrangement • MLL rearrangement