BMF (Bcl2 Modifying Factor)

DNTTIP1 is overexpressed in acute leukaemia and associated with poor prognosis. DNTTIP1 acts as a scaffold for the MiDAC complex, recruiting HDAC1/2 to silence BMF and inhibit leukaemic cell death. Pharmacological disruption of the DNTTIP1-HDAC1/2-BMF axis impairs leukaemogenesis.

Accordingly, EZH2 inhibitors cooperated with genetic or pharmacological inhibition of YAP/TEAD, which similarly induced BMF expression and apoptosis. Together, these findings show how EZH2 and YAP/TEAD coordinately insulate the BMF locus and demonstrate that EZH2 inhibitors can be used to reprogram HER2+ tumors, resulting in a dramatic sensitization to HER2 kinase inhibitors and enhanced killing of residual disease.

Despite this progress, further studies are needed to resolve context-dependent functional discrepancies, validate biomarker utility, and develop cell-specific delivery systems. This review provides a framework to understand its pathophysiologcial roles and potential application as a biomarker and therapeutic target.

Our results suggest that PANoptosis of macrophages promotes the development of ALF. The seven new ALF biomarkers identified and validated in this study may contribute to further investigation of diagnostic markers or novel therapeutic targets of ALF.

Furthermore, SCRN2 decreases the expression of key DNA repair-related genes and induces endogenous DNA damage, thus conferring therapeutic sensitivity of TNBC cells to PARP inhibition.   Collectively, these findings identify SCRN2 as a novel suppressor of TNBC, reveal its mechanism of action, and highlight its potential role in TNBC therapy.

The latter group of cases with a recessive genetic pattern (GG vs. GC+ CC) showed enhanced susceptibility to promoting PDAC (OR = 1.7; 95% CI: 1.2-2.9; p = 0.04). Our findings indicate that genetic variation in CDKN2A was linked to the susceptibility of extending PDAC, suggesting the need for additional research in a broader, multi-center context to approve the possible significance of this gene as a novel indicator for the stratification of PDAC.

Knockdown of YAP and overexpression of BMF attenuated pressure-mediated stemness and tumorgenicity, while YAP-deficient and BMF-deletion recused pressure-dependent stemness on LCSCs, suggesting the involvement of YAP/BMF signaling axis in this process. Together, our findings provide a potential target for overcoming the stemness of CSCs and elucidate the significance of increased IFP in cancer progression.

Accordingly, cell death can be prevented by activating β-catenin, blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant CRCs and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.

Knockdown of YAP or overexpression of BMF significantly attenuated matrix stiffening-induced stemness, suggesting the involvement of YAP and BMF in this process. Together, our results unravel the regulatory mechanism of heterogeneous matrix stiffness on CSC stemness and also provide a novel therapeutic strategy for eradicating CSCs and improving the efficiency of HCC treatment.

The study is open to enrollment and registered at ClinicalTrials. gov (NCT05665530).

In a similar fashion, Venetoclax-driven BCL2 inhibition also potentiated the anti-tumor activity of PRT2527...Additionally, we demonstrated that PRT2527 potently inhibits growth in Ibrutinib-resistant MCL cell lines. Further work characterizing PRT2527 as monotherapy and in combination with BTKi and BCL2i in in vivo models of BTKi-resistant MCL and CLL is currently ongoing. Altogether these data provide a rationale for evaluating PRT2527 in combination with BTK and BCL2 inhibitors for the treatment of patients with relapsed/refractory hematologic malignancies.

Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.