KMT2A (Lysine Methyltransferase 2A)

NLR ≥3 and the presence of liver metastases were identified as independent prognostic factors. These preliminary findings may help refine prognostic stratification for advanced melanoma patients receiving immunotherapy.

As a result, we found that any possible 2-drug combination of venetoclax, ponatinib, and trametinib was highly synergistic in vitro. Regrettably, none of the synergistic 2-drug combinations appeared sufficiently effective in preventing leukemia outgrowth in our PDX models, which likely requires combinations of >2 drugs. Hence, our results illustrate/signify that straightforward high-throughput combinatorial drug screening in leukemia cell lines is a valid approach to identify synergistic drug combinations that are verifiable in vivo in PDX mouse models without requiring validation in primary patient cells in vitro.

Clinical activity observed with menin inhibitors provides translational validation of this dependency and establishes menin inhibition as a differentiation-based therapeutic strategy. In this review, we examine the molecular basis of menin-dependent transcriptional regulation in AML and its implications for therapeutic targeting with menin inhibitors and resistance to therapy.

Gene set enrichment analysis (GSEA) indicated enrichment of MAPK signaling, AP-1-mediated stress response, and epithelial-mesenchymal transition (EMT)/migration-associated pathways in CD68-high models. Together, these findings suggest that CD68 contributes to a pro-tumorigenic and stress-adaptive phenotype in pedAML and may represent a biologically relevant therapeutic target.

This combination was associated with high response rates and durable remissions, with an acceptable safety, in heavily pretreated patients with AML harboring alterations susceptible to menin inhibition.

P1, N=38, Recruiting, National Cancer Institute (NCI) | N=28 --> 38

P2, N=90, Not yet recruiting, SWOG Cancer Research Network

P1, N=23, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2026 --> May 2027 | Trial primary completion date: May 2026 --> May 2027

Combination therapy with MI plus hypomethylating agent and venetoclax produced higher CR (43.3% vs 19.5%; p = 0.002) and CR+CRh rates (48.6% vs 25.8%; p = 0.007) than monotherapy...Differentiation syndrome occurred in 14.6%, and treatment-related mortality in 5.0%. MI-based therapy demonstrates meaningful activity in heavily pretreated AML, with deeper responses observed using combination strategies.

Conventional karyotyping and targeted FISH probes were employed to identify recurrent and rare chromosomal abnormalities, with a special emphasis on inv(16) (p13.1q22), MLL rearrangements, and complex karyotypes. Our findings highlight the indispensable role of integrating cytogenetics and FISH in routine diagnostic workflows, especially in cases with cryptic rearrangements or subclonal abnormalities, thereby underscoring their clinical and prognostic significance.

Here, we define a clinically actionable strategy that functionally targets PLK1 by combining inhibition of the AAA+ ATPase p97/valosin-containing protein (VCP) with the hypomethylating agent decitabine (DAC). In vivo, CB-5339/DAC is well tolerated, significantly prolongs survival, reduces leukemic burden, and suppresses PLK1 in bone marrow blasts. Together, these data establish p97 inhibition as a rational means to exploit replication and proteotoxic stress in AML and provide strong rationale for clinical evaluation of CB-5339 plus DAC in high-risk disease.