SETBP1 (SET Binding Protein 1)

Patients with JAK2V617F- and CALR-unmutated ET tend to present at a younger age and exhibit a lower incidence of thrombosis compared to those with JAK2V617F-mutated ET. The application of WES enabled the detection of uncommon and potential driver mutations in JAK2V617F- and CALR-unmutated ET.

To establish the efficacy of MYST inhibition in vivo , we treated mice harboring a syngeneic SETBP1 -mutant leukemia with the clinical-grade MYST inhibitor-PF-9363...In this study, we identify MYST acetyltransferases as key drivers of mutant SETBP1-driven transcription. MYST inhibitors are highly effective against SETBP1-mutant leukemia and represent a promising avenue for clinical translation.

The most used agents include hydroxyurea, interferon, hypomethylating agents, and JAK inhibitors, although none of them are disease-modifying. Allogeneic hematopoietic stem cell transplant remains the only potentially curative approach and should be considered in all eligible patients. Actionable mutations (CSF3R, NRAS/KRAS, and KIT) have also been identified, supporting the development of new agents targeting the involved pathways.

Platelet-derived growth factor receptor beta (PDGFRB)-rearranged myeloid/lymphoid neoplasms (MLNs) are rare hematologic malignancies typically responsive to tyrosine kinase inhibitors (TKIs) such as imatinib. The patient progressed to acute myeloid leukemia (AML) within 11 months despite sequential therapies including dasatinib and azacitidine-venetoclax, ultimately succumbing to sepsis. This case highlights the limitations of TKI monotherapy in MLNs with PDGFRB rearrangements and co-existing high-risk mutations, underscoring the importance of early molecular profiling and consideration of allogeneic hematopoietic stem cell transplantation in cases with poor risk features.

Notably, SETBP1 mutation plays a dominant role in establishing a stable chromatin accessibility landscape, even when co-occurring with ASXL1. Our study establishes an iPSC-based model of GATA2 deficiency, offering new insights into myeloid disease progression and a platform for testing future therapeutic strategies.

For predicting OS, IWG molecular classification had a Harrell's C-index of 0.75, compared with WHO5 and ICC Harrell's C-indices of 0.74 and 0.73, respectively. Altogether, these results show that the IWG molecular taxonomy can be applied in routine practice, with several classes exhibiting distinct clinical features and outcomes.

Notably, 5 of 10 der(7) cases with follow-up evolved to -7. Der(7) defines a distinct high-risk subgroup with a unique molecular profile and poor prognosis comparable to -7.

This research enhances our understanding of the genetic risk factors for breast cancer in the Pashtun population and underscores the potential importance of the SETBP1 rs11082414 variant in identifying individuals at risk. The identification of genetic biomarkers can facilitate the development of targeted drug therapies, improve early detection, and enhance the effective management of breast cancer.

The findings of this study provide a comprehensive understanding of MF's molecular profile. The discovery of commonly mutated pathways (Wnt, p53, JAK/STAT, and epigenetic regulators) suggests potential targets for the development of future therapies. Furthermore, the enrichment of certain mutations based on race and patterns of alteration co-occurrence offer possibilities for patient-tailored treatment approaches.

Transcriptomic profiles of GATA2-mutant cells revealed that these functional defects are associated with reduced HSC self-renewal capacity and upregulation of the pre-aging phenotype. Our work highlights the feasibility of generating a human GATA2 deficiency model suitable for studying the biological consequences of various GATA2 variants and the generation of a platform to test potential phenotype-rescuing therapeutics.

P1/2, N=44, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2025 --> Sep 2027 | Trial primary completion date: Sep 2025 --> Sep 2027

Co-treatment with rapamycin and DS-5272 had a dramatic in vivo effect on MLL-AF9-driven AML, curing 85% of the leukemic mice. Thus, machine learning-based predictive approaches identified monocytic AML with wild-type TP53 and low Rapa-11 score as a rapamycin-sensitive AML subtype and an ideal target for mTOR/p53 co-targeting therapy.