This study identifies WNK1 as a key oncogenic driver in AML and establishes WNK1 inhibition as a promising therapeutic strategy that not only suppresses AML progression but also sensitizes leukemia cells to venetoclax. These findings provide a rationale for novel combination regimens to overcome drug resistance in AML.

To report a rare case of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) presenting with acute gastrointestinal perforation and to describe the use of an exploratory regimen combining a BCL-2 inhibitor (Venetoclax) with CHOP chemotherapy, highlighting the diagnostic challenges and therapeutic considerations for this aggressive disease...Besides, the prolonged untreated interval observed in this patient highlights the potential biological heterogeneity of MEITL. While the observed complete metabolic remission is encouraging, this finding remains hypothesis-generating and requires validation in larger studies.

This review evaluates BCL-2 primarily as a prognostic, treatment-stratifying, and venetoclax-related predictive biomarker in leukemia, while critically examining its more limited and context-dependent diagnostic contribution...To move BCL-2 assessment into routine laboratory practice, it will be necessary to establish harmonized thresholds for BCL-2 assays and to validate the analytical workflow and result in prospective studies. This review outlines the potential and current challenges of BCL-2 as an emerging biomarker in human leukemia within a laboratory medicine framework.

APLL is characterized by significant endothelial damage, which is quantifiable by EASIX to independently contribute to the elevated MBE risk. The EASIX-based stratification can be utilized to rapidly identify high-risk APLL, who may benefit from an optimized VEN-HMA induction strategy to reduce ED risk.

YY‑20394 (linperlisib), a highly specific PI3Kδ inhibitor, has demonstrated promising efficacy in a variety of hematological malignancies in clinical trials. In summary, YY‑20394 is effective for inhibiting proliferation of AML cells, and its combination with ABT199 has synergistic pro‑apoptotic effects in MV‑4‑11 cells, which provides new insights and potential avenues for the treatment of AML and its subtypes. Further studies are warranted to explore the therapeutic efficacy and underlying molecular mechanisms of this combination in additional AML subtypes.

P3, N=60, Completed, The First Affiliated Hospital of Soochow University | Recruiting --> Completed | N=30 --> 60 | Trial completion date: Mar 2025 --> Feb 2026

The cytotoxic and antifibrotic effects of the BCL-XL inhibitor ABT-263 (navitoclax), alone or combined with the JAK2 inhibitor ruxolitinib, were evaluated in stromal and hematopoietic contexts. Combined inhibition of BCL-XL and JAK2 produced synergistic antifibrotic and pro-apoptotic effects in MSCs, post-MPN acute myeloid leukemia (AML) cell lines, and patient-derived cells resistant to ruxolitinib. Collectively, these findings identified BCL-XL as a key mediator of MPN-associated fibrosis and therapeutic resistance, and confirmed dual targeting of BCL-XL and JAK2 as a rational strategy for advanced MPN.

The NAMPT inhibitor KPT-9274 combined with BCL2 inhibitor venetoclax was particularly effective at targeting MDS blasts compared to NAMPT inhibition alone. MDS samples with -7/-7q also showed significantly lower NAMPT expression compared to the non -7/-7q samples, indicative of haploinsufficient gene expression profile. In conclusion, these findings support NAMPT haploinsufficiency as a vulnerability and as biomarker for NAMPT inhibitor activity in -7/-7q MDS.

P3, N=400, Recruiting, Ascentage Pharma Group Inc. | Trial primary completion date: Oct 2025 --> Dec 2026

P2, N=32, Not yet recruiting, Peking University People's Hospital

P1/2, N=53, Recruiting, Columbia University | Trial completion date: Sep 2026 --> Sep 2027 | Trial primary completion date: Sep 2026 --> Sep 2027

Overexpression of anti-apoptotic protein BCL-2 and hypermethylation are hallmarks of acute lymphoblastic leukemia (ALL) and can be pharmacologically addressed by venetoclax (VEN) and hypomethylating agents (HMA) such as azacytidine (AZA) or decitabine (DEC). AZA-induced metabolic suppression as well as overall anti-leukemic activity alone and in combination with VEN was generally weaker compared to DEC. Altogether, we herein demonstrate that combined VEN and HMA application acts synergistically and significantly reduces the leukemic burden in ALL cell lines via impairment of tumor cell metabolism and mitochondrial function.