KMT2A mutation

We recently demonstrated that INO can be added safely to a non-myeloablative conditioning of bendamustine, fludarabine, and rituximab in patients with indolent lymphoid malignancies who required an allogeneic hematopoietic transplantation (HCT) (Am J Hematol 2024)...Patients who received transplants from MUDs received an additional dose of methotrexate 5 mg/m2 on day +11 and 1 mg/kg of rabbit anti-thymocyte globulin IV on days -1 and -2 before HCT...The patient who was in CR2 at transplant had Ph+ ALL and was maintained on ponatinib after HCT. Key prior therapies in ALL patients included blinatumomab (n=5) and INO (n=5)...The survival outcomes are encouraging and need to be validated in a larger number of patients. Currently, post-transplant cyclophosphamide has been implemented to lessen the risk of GVHD.

Therefore, new drug discovery strategy should be considered in advance. The expert opinion was proposed from several aspects, such as developing diverse chemical structures, discovering covalent inhibitors, designing small molecular PROTACs, and targeting the amino acids mutations for next-generation inhibitors.

In 2002, Allis and colleagues first characterized the lysine methyltransferase activity of the mammalian KMT2A (MLL1), a paradigm shifting discovery that brings epigenetic dysregulation into focus for many human diseases that carry KMT2A mutations. This review will discuss the current understanding of the multifaceted roles of KMT2A in development and disease, which has paved the way for innovative and upcoming approaches to cancer therapy.

KMT2A mutations (hazard ratio [HR], 4.47; 95% confidence interval [CI], 1-19.93; P =0.050) and dMMR signature proportions (HR, 3.57; 95% CI, 1.42-8.96; P = 0.007) remained independently associated with PFS after multivariate analysis and the results were further externally validated. These findings may enhance our understanding of this disease and may potentially facilitate the optimization of its treatment approaches.

P1/2, N=90, Recruiting, BioNova Pharmaceuticals (Shanghai) LTD. | Not yet recruiting --> Recruiting

P1, N=171, Recruiting, Kura Oncology, Inc. | Not yet recruiting --> Recruiting

P1, N=212, Recruiting, Kura Oncology, Inc.

Notably, patients with the immune dysregulation subtype were sensitive to immunotherapy and chemotherapy. Collectively, our findings suggest that mA modification could be a potential therapeutic target for AML, and the identified subtypes could guide personalized therapy.

The treatment options for patients with AML have expanded for specific molecular subsets such as FLT3 and IDH1/2 mutated AML, with development of novel agents for NPM1 mutated or KMT2A rearranged AML ongoing, but also due to effective venetoclax-combinations. Evidence regarding highly sensitive molecular MRD detection methods for specific molecular subgroups, in the context of these new treatment approaches, will likely shape the future of AML care.

In addition, we demonstrated that NPM1 mutation remains favorable in patients treated with HMA + Ven. Our findings help contribute to the ever-growing, complex molecular and genomic profiling of AML patients.

Therefore, some KMT2A-PTD variants could be potentially implemented in AML risk stratification. However, prospective studies and larger patient numbers are needed.

P1/2, N=90, Not yet recruiting, BioNova Pharmaceuticals (Shanghai) LTD.

P1, N=171, Not yet recruiting, Kura Oncology, Inc.

PCa patients with a tobacco smoking history demonstrated a significantly higher frequency of somatic genetic mutations. Whereas mutations of PREX2, KMT2C, AGO2, and PTEN genes were higher in smokers, the APC and KMT2A mutations were higher in nonsmokers. The PTEN somatic gene mutation was associated with increased overall mortality among patients with PCa irrespective of smoking history. We found that G129R PTEN mutation known to reduce the PTEN phosphatase activity and K267Rfs*9 a frameshift deletion mutation in the C2 domain of PTEN associated with membrane binding exclusively detected in smokers and nonsmokers, respectively. These findings may be used to further our understanding of PCa associated with smoking.

P1, N=212, Recruiting, Kura Oncology, Inc. | Not yet recruiting --> Recruiting

There are several small molecule inhibitors that have demonstrated promise in these high-risk AML subsets. Longer follow up and ongoing investigation is needed to continue to optimize therapy for patients with high-risk AML.

We also discuss how altered condensate formation contributes to malignant transformation of hematopoietic cells, as described for promyelocytic leukemia protein (PML) in PML::RARA-driven acute promyelocytic leukemia (APL) and other myeloid malignancies. Finally, we discuss potential strategies for interfering with the molecular mechanisms related to AML-associated biomolecular condensates, as well as current limitations of the field.

Children with B-ALL are prone to genetic mutations, with abnormalities in the RAS signaling pathway being the most common. Signal transduction related PTPN11, JAK2 and JAK3 gene mutations, epigenetic related KMT2A gene mutation and transcription factor related BCORL1 gene mutation are independent risk factors for MRD.

He was started on CapOx with Bevacizumab and developed gastric outlet obstruction...The results suggested that these mutations have not been reported in gastric cancer earlier and despite not having a direct pathway of carcinogenesis they probably act through modulation of host of miRNA's. Further studies are needed to investigate the role of KMT2A, LTK, and MST1R gene in gastric carcinogenesis.

We evaluated the combination of RAS/MAPK pathway inhibition by the MEK1/2 inhibitor selumetinib with the Menin inhibitor VTP-50469 (SNDX-5613) in a genetically defined, poor prognostic subgroup of pediatric leukemia harboring KMT2A-r with RAS mutations. The findings in our preclinical study suggest a promising, readily translatable treatment for patients with KMT2A-racute leukemias harboring RAS mutations. Mechanistically, enhanced downregulation of both MYC signaling and the RAS/MAPK pathway with the combinatorial therapy is likely a strong contributor to the observed efficacy. MYC, Acute leukemia, KMT2A

No abstract available

We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.

P1, N=212, Not yet recruiting, Kura Oncology, Inc.

We also observe that PHDs of KMT2A-D are mutated in cancer, especially within conserved folding motifs (Cys4HisCys2Cys/His). The mutations cause a domain loss-of-function. Taken together, our data suggest that PHDs of KMT2A-D guide the full-length proteins to active promoters and enhancers, and thus play a role in positive transcriptional memory.

This is the largest study comparing outcomes of MDS/CMML patients with and without spliceosome mutations undergoing allo-HCT. Our study shows better overall survival in patients who have spliceosome mutations due to lower non relapse mortality compared with non- spliceosome mutations patients after allo-HCT. Figure1.

Additionally, the study will evaluate the impact of MRD, as measured by central flow cytometry and next-generation sequencing of NPM1 mutations. Additional evaluations and biomarkers of potential interest include menin- KMT2A-specific transcriptomic changes, myeloid differentiation/cell subset changes, mechanisms of resistance, and discovery of baseline features (methylation, mutations, etc.) that can impact outcomes.

Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org. Clinicaltrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00899223 (CALGB 9665), NCT00900224 (CALGB 20202).

The complex karyotype with clonal evolution and mutations in KMT2A, KRAS, NRAS, and SUZ12 indicates a poor prognosis. We hypothesize that the CA detected may be a cause of the unique pathological features of this case. More reports can help test this hypothesis and confirm if the CA may be markers for diagnosis, prognosis, and treatment of this type of tumor.

Targetable mutations are frequent in EM-AML and EM-site NGS is warranted for selecting potential targeted therapies for patients with EM-AML.

Here we investigated the links between ABC activity, as evaluated by JC-1 +/- cyclosporine A (CsA) assay, and immunophenotypic, cytogenetic, molecular, and targeted next generation sequencing features in 361 AML patients...In the 230 patients evaluated at diagnosis and intensively treated, high ABC activity was a predictive factor for primary resistance, and in multivariate analysis including full molecular data, an independent factor for event-freesurvival (p=0.0370). JC-1 +/- CsA assay could be used at diagnosis to predict AML ontogeny and to complete prognosis evaluation in addition to new molecular markers.

Collectively, we identified that KMT2 family mutations were correlated with higher-TMB and higher-MSI, thus resulting in a better outcome for colorectal cancer patients.

Conclusion Molecular profiling of KMT2A -rearranged AML in Russian Federation reveals the highest incidence of KMT2A-MLLT3 fusion gene and KMT2A intron 9 involvement. Our data also confirms the relatively quiet landscape of accompanying mutations in KMT2A-rearranged AML with RAS pathway most frequently involved.

In a multivariable analysis, FLT3 non-ITD mutations were not an independent prognostic factor. However, patients with dual FLT3 non-ITD and KMT2A-PTD mutations showed a trend for inferior outcome, which points at a functional interaction in this subset of AML.

LSDC is a very rare and highly aggressive salivary-type malignant tumor. The postoperative diagnosis mainly depends on histopathology and immunohistochemistry, attention should be paid to differential diagnosis to prevent missed diagnosis.

Cerebral vasculitis was treated with steroids, cyclophosphamide and required ventriculoperitoneal shunting...She received a conditioning regimen based on treosulfan, fludarabine, thiotepa and rabbit anti-thymocyte globulin. Tacrolimus and methotrexate were used as graft versus host disease (GVHD) prophylaxis... We would like to highlight the important role that has played in the haematological recovery of our patient both the immunospurression stop and the splenectomy. CBL is a rare syndrome and very few transplant cases have been reported, but data suggests that HSCT not only can prevent developing JMML but it also improves cerebral vasculitis. Further investigation should be conducted on this topic.