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BIOMARKER:

MLL rearrangement

News alerts, weekly reports and conference planners

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.

1 day ago

Review • Journal

WDR5 (WD Repeat Domain 5)

MLL rearrangement

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.

3 days ago

Preclinical • Journal

KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement

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.

5 days ago

Journal

CD34 (CD34 molecule) • AURKA (Aurora kinase A) • PLK1 (Polo Like Kinase 1)

MLL rearrangement

volasertib (NBL-001) • alisertib (MLN8237)

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.

5 days ago

Review • Journal

KMT2A (Lysine Methyltransferase 2A) • BRD4 (Bromodomain Containing 4) • DOT1L (DOT1 Like Histone Lysine Methyltransferase)

MLL rearrangement • MLL fusion

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.

5 days ago

Preclinical • Journal • Circulating tumor DNA

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement

10d

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

10 days ago

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

15d

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.

15 days ago

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

16d

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.

16 days ago

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

17d

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.

17 days ago

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

24d

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.

24 days ago

Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1)

NPM1 mutation • MLL rearrangement

25d

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.

25 days ago

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

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

1 month ago

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)

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.

1 month ago

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

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.

1 month ago

Journal

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement • MLL rearrangement • MLL fusion

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.

1 month ago

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

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

1 month ago

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)

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.

1 month ago

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)

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.

1 month ago

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

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.

2 months ago

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

2 months ago

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.

2 months ago

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.

2 months ago

Journal • IO biomarker

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)

MLL rearrangement • MLL rearrangement • BCL2 expression • BAX expression

JQ-1 • Epidaza (chidamide)

2ms

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.

2 months ago

Journal

KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2)

KMT2A rearrangement • MLL rearrangement • CRLF2 rearrangement

2ms

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.

2 months ago

Journal

NSD3 (Nuclear Receptor Binding SET Domain Protein 3) • NSD2 (Nuclear Receptor Binding SET Domain Protein 2)

MLL rearrangement

2ms

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.

2 months ago

Review • Journal

ZNF501 (Zinc Finger Protein 501)

MLL rearrangement • Chr t(9;11)

2ms

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.

2 months ago

Review • Journal

KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement

2ms

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.

2 months ago

Journal

KMT2A (Lysine Methyltransferase 2A) • KAT6A (Lysine Acetyltransferase 6A) • MLLT3 (MLLT3 Super Elongation Complex Subunit)

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.

3 months ago

Journal

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)

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.

3 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement

3ms

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.

3 months ago

Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

NPM1 mutation • MLL rearrangement • MLL rearrangement • MLL fusion

3ms

Selective inhibition of HDAC class IIA as therapeutic intervention for KMT2A-rearranged acute lymphoblastic leukemia. (PubMed, Commun Biol)

Finally, LMK-235 appeared to exert minimal anti-leukemic effects in vivo in combination with the BCL-2 inhibitor venetoclax, but not enough to prolong survival in treated mice. In conclusion, class IIA HDAC isoforms represent attractive therapeutic target in KMT2A-rearranged ALL, although clinical applications require the development of more stable and efficient specific HDAC inhibitors.

3 months ago

Journal

KMT2A (Lysine Methyltransferase 2A) • HDAC5 (Histone Deacetylase 5) • HDAC4 (Histone Deacetylase 4) • HDAC7 (Histone Deacetylase 7)

MLL rearrangement

Venclexta (venetoclax)

3ms

Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial. (PubMed, Lancet Oncol)

Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing.

3 months ago

P1 data • Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

NPM1 mutation • KMT2A rearrangement • MLL rearrangement • MLL mutation

ziftomenib (KO-539)

3ms

Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia. (PubMed, Hemasphere)

Human KMT2A-r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels...Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.

3 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • STAT5A (Signal Transducer And Activator Of Transcription 5A) • NKG2D (killer cell lectin like receptor K1)

RAS mutation • KMT2A rearrangement • MLL rearrangement • NRAS G12D • NRAS G12 • FLT3 N676K • MLL mutation • KMT2A expression

Farydak (panobinostat)

3ms

Pretransplant MRD detection of fusion transcripts is strongly prognostic in KMT2A-rearranged acute myeloid leukemia. (PubMed, Blood)

Pre-transplant detection of KMT2Ar MRD ≥0.001% by quantitative PCR was associated with significantly inferior post-transplant survival (2-year RFS 17% vs 59%; p=0.001) and increased cumulative incidence of relapse (2-year CIR 75% vs 25%, p=0.0004).

3 months ago

Journal • Pre-transplantation

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement

3ms

Dexamethasone Inhibits the Growth of B-Lymphoma Cells by Downregulating DOT1L. (PubMed, Cancer Rep (Hoboken))

Overall, our findings indicated that DOT1L may serve as a potential drug target and a promising biomarker of Dex sensitivity when it comes to treating B lymphoma.

3 months ago

Journal

DOT1L (DOT1 Like Histone Lysine Methyltransferase)

MLL rearrangement

dexamethasone

3ms

Trial Evaluating MGTA-456 in Patients With High-Risk Malignancy (clinicaltrials.gov)

P2, N=22, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2024 --> Jun 2025

3 months ago

Trial completion date

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha)

FLT3-ITD mutation • NPM1 mutation • MLL rearrangement • MLL rearrangement • CEBPA mutation • FLT3 wild-type

cyclophosphamide • melphalan • fludarabine IV • busulfan • spanlecortemlocel (MGTA-456)

3ms

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: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

3 months ago

Trial completion date • Trial primary completion date • Post-transplantation

FLT3 (Fms-related tyrosine kinase 3) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1)

MLL rearrangement • Chr t(9;11)

cyclophosphamide • fludarabine IV

3ms

Pitfalls in Diagnosis: JMML versus KMT2A Rearranged Juvenile AML. (PubMed, Case Rep Hematol)

This case highlights the challenges of diagnosing KMT2A-rearranged monocytic AML and the importance of careful morphological assessment in partnership with cytogenetic and molecular diagnostics to distinguish between KMT2A-rearranged AML and JMML. Moreover, the emerging role of molecular monitoring in AML is highlighted.

3 months ago

Journal

KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement

3ms

Outcomes with single-agent gilteritinib for relapsed or refractory FLT3-mutant AML after contemporary induction therapy. (PubMed, Blood Adv)

Gilteritinib is the current standard of care for relapsed or refractory FLT3-mutated AML in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or non-intensive chemotherapy with venetoclax) are uncertain. Twenty patients received gilteritinib as first salvage having progressed following first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials but outcomes remain suboptimal, with more effective strategies needed.

3 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A)

FLT3 mutation • RUNX1 mutation • KMT2A rearrangement • MLL rearrangement

Venclexta (venetoclax) • Xospata (gilteritinib) • Rydapt (midostaurin)

3ms

Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study. (PubMed, Leukemia)

Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse.

3 months ago

Journal

RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • TCF3 (Transcription Factor 3) • PBX1 (PBX Homeobox 1)

KMT2A rearrangement • MLL rearrangement

7ms

Immune escape of B-cell lymphoblastic leukemic cells through a lineage switch to acute myeloid leukemia. (PubMed, Leuk Lymphoma)

Forty patients (37.7%) received lineage-specific immunotherapy. Our findings suggest that the prevalence of KMT2A rearrangements together with the lineage-specific immunotherapy may trigger LS, which supports the thesis of the existence of leukemia stem cells that are capable of lymphoid or myeloid differentiation.

7 months ago

Journal

KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement

7ms

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.

7 months ago

Journal

DOT1L (DOT1 Like Histone Lysine Methyltransferase) • MLLT3 (MLLT3 Super Elongation Complex Subunit)

MLL rearrangement • MLL fusion