SF3B1 mutation

No abstract available

Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.

P2, N=80, Recruiting, Mayo Clinic | N=55 --> 80

Not available.

Curiously, although modestly varying among AML samples, a high AKT1 expression shows in contrast as a strong predictor of a better patient outcome. These data suggest that AKT3 and AKT1 expressions have strong, yet opposite, prognostic values.

Therefore, TrkAIII splicing is common in PitNETs, is elevated in invasive, especially PIT1 tumors, can result in intracellular TrkAIII activation, and may involve hypoxia. The data support a role for TrkAIII splicing in PitNET pathogenesis and progression and identify TrkAIII as a novel potential target in refractory PitNETs.

Together, our work provides mechanistic insights that link ISC deficiency to cuproptosis, as exemplified by the high sensitivity of SF3B1-mutated AMLs. We thus propose SF3B1 mutations as a biomarker for future copper ionophore-based therapies.

Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.

P2, N=55, Recruiting, Mayo Clinic | Trial completion date: Mar 2024 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Dec 2025

P1, N=52, Recruiting, Massachusetts General Hospital | Trial primary completion date: May 2022 --> May 2024

Our study first investigated the role of centrosome-related genes in UVM overall survival (OS). We then constructed a centrosome-related gene signature for UVM, which provides new insights into the role of CA in UVM and identifies novel centrosome-related biomarkers.

Exclusion of patients not meeting ICC-criteria for MDSSF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutationbased, disease classification for MDS-RS might be prognostically more relevant.

Gene mutation is closely related to cytogenetic indexes and clinical features (peripheral blood cell count, sex, age). IPSS-R prognostic score and TP53 were risk factors affecting OS in MDS patients.

In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

P1, N=127, Terminated, Hemavant Sciences GmbH | N=200 --> 127 | Trial completion date: Dec 2024 --> Feb 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2024 --> Feb 2024; The study was terminated after conducting an interim analysis of the available data where it became evident that the observed efficacy results were not in alignment with the initially set expectations.

P1/2, N=39, Recruiting, University of Utah | Suspended --> Recruiting

MDS patients with DM have an inferior prognosis which may due to higher infection incidence, with TET2 and SF3B1 mutations being more frequent in those cases.

The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Additionally, the study developed a risk score based on gene mutation data that demonstrated robust predictive capability and stability for the overall survival of MDS patients. Our research provided a strong theoretical basis for the establishment of personalized treatment and prognostic risk assessment models for Chinese MDS patients.

Our data confirmed a reduced CD20 expression in CLL patients with NOTCH1 and SF3B1 mutations. In addition, an approach was proposed to identify high-risk CLL patients for prediction of such mutations: previously untreated CLL patients at advanced Binet - Rai stages (BII, CIII, CIV) with a reduced number of double-positive CD20+CD5+ cells in peripheral blood and/or low iMFI of CD20+ cells.

Cancer-derived mutations in SF3B1 damage its association with PRP5, compromising BS proofreading. Together, these findings reveal key insights into prespliceosome assembly and BS selection or proofreading by PRP5.

Thus, gain of chromosome 8q has additional predictive value for BAP1 tumors, but not for SF3B1 tumors. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

These data demonstrate the clear ability of the 2022 WHO and ICC classifications to organize MDS patients into distinct prognostic risk groups and further show that both classification systems share more similarities than differences. Incorporation of the IPSS-M and IPSS-R features provide additive prognostic and survival components to both the WHO and ICC classifications, which together enhance their utility for evaluating and treating MDS patients.

Interaction with SF3B1 exposes the G-patch domain of SUGP1, facilitating binding to and activation of DHX15. The model can explain the activation of cryptic 3' splice sites induced by mutations in SF3B1 or SUGP1 frequently found in cancer.

Median survival was 11.7 versus 4 years (5/10-year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia-free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision-making in MDS-del(5q) regarding allogeneic stem cell transplant.

Although the patient's blood counts initially responded to ruxolitinib and hydroxyurea, the response was not durable. Early referral for allogenic bone marrow transplant appears necessary to prevent long-term complications and disease progression in myeloid neoplasms with clonal hypereosinophilia driven by noncanonical JAK2 mutations.

The two new diagnostic classifications include MDS defined by mutations in SF3B1 and TP53, though there are differences in diagnostic criteria. Future efforts to refine MDS prognostication could investigate the interface between MDS and clonal cytopenia of undetermined significance, expand access to genomic testing, obtain results in a less invasive manner, and develop treatment-response predictors and dynamic risk models.

Although options for reducing the transfusion burden have recently been improved, erythropoiesis-stimulating agents (ESAs), lenalidomide, hypomethylating agents, and, more recently, luspatercept have shown efficacy in rarely more than 50% of patients with a duration of response often far inferior to the patient's life expectancy. Targeting ligands of the transforming growth factor β pathway has led to the approval of luspatercept in LR-MDS with ring sideroblasts or SF3B1 mutation, potentially replacing first-line ESAs in this population. Here, we also discuss the evolving standard of care for the treatment of LR-MDS and explore some of the most promising next-generation agents under investigation.

Our results show that clonal evolution is active even without therapy pressure and that repeated genetic testing can be clinically relevant during long-term patient monitoring. Moreover, integrative NGS testing contributes to the consolidated evaluation of results and accurate assessment of individual patient prognosis.

This is the largest molecular profiling analysis of PASC, which is characterized by unique genomic alterations, and is associated with higher PD-L1 expression, immune related gene expression, CD4+ T cell infiltration and IFN gamma signature, and lower MAPK activation. PASC is associated with better OS compared to PSCC. These findings may provide subtype-specific therapeutic opportunities for PASC and PSCC pts.

We experimentally evaluated the anti-tumor effects of these neoepitopes and found they induced robust immune responses by stimulating interferon (IFN production and activating T cell-based UM tumor killing. These results provide novel insights into UM-specific neoepitopes independent of SF3B1 and lay the foundation for developing therapies by targeting these actionable neoepitopes.

Although great progress has been made in the understanding of MPN clonal hematopoiesis and its evolution with the development of next-generation sequencing, there are still many limitations. In this study, we mainly discuss gene mutations of MPN and their influences on the thrombosis, leukemia and fibrosis transformation, and the influencing factors of clonal evolution, aiming to summarize the influence of clonal hematopoiesis and its evolution on the complications, prognosis and survival of MPN.

Post transplant treatment included lenalidomide maintenance, followed by a variety of salvage regimens over the next 7 years including thalidomide, carfilzomib, daratumumab and pomalidomide...He received a second ASCT after melphalan 140 mg/m2 in Oct 2017 followed by recovery of normal blood counts...Case 3 = 65-year-old man with MM treated with bortezomib + dexamethasone followed by ASCT in Aug 2012...Six months of decitabine did not improve his blood counts...This approach was well tolerated and provided durable hematopoietic recovery. Second ASCT using banked autologous stem cells should be considered in such patients who are not otherwise candidates for allogeneic transplantation.

We identified a highly potent TCR that eliminates cancer cells while sparing mutation negative cells. These data support further development of this TCR as a potential therapeutic for MDS and AML.

Key exclusion criteria include a diagnosis of acute myeloid leukemia, history of intracranial hemorrhage or risk of major hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or history of treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. Patients with platelet count ≥ 25 x 10 9/L and < 75 x 10 9/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. This study will open at 7 sites in the United States and is anticipated to open in January 2024.

In conclusion, by assessing the individual contribution of DME and TL to disease survival, we found that both variables offer valuable independent prognostic information when included in statistical models with poor-risk genomic lesions. TL and DME could help identify IGHV-mutated patients destined to respond poorly to (immuno-)chemotherapy, that might be more favourably treated with targeted agents.

The identification of both morphologic and molecular abnormalities in our cohort may inform therapeutic considerations as well as vigilance for the discovery or evolution of myeloid disorders during follow-up , in particular when unexpected cytopenias or new clinical concerns emerge. We expect to design future prospective studies, based on our observations, to further inform of the risk of myeloid disorders in our plasma cell disorder patient cohorts, as well as understand its impact on therapies such as immunomodulatory agents, alkylators and/or autologous stem cell transplant.

This is the first study to describe the genomic landscape of patients with B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib. Here we show that the gene mutational profile of these patients at baseline or at/after disease progression is comparable with patients with relapse/refractory disease who tolerate ibrutinib and, consistent with other studies, patients with mutations in TP53, SF3B1 or ATM genes had less favorable prognosis on BTKi. Further, intolerant patients who progressed on zanubrutinib acquired new BTK mutations and/or had an increase in the frequency of BTK mutations.

This study shows us that there are more mutations associated with therapeutic failure in patients with CML in addition to those in the ABL domain. Knowing these mutations can support the diagnosis, prognosis, establish target therapies and even guide the decision of a bone marrow transplant. Studies with larger populations are required to corroborate the data presented here to generate correlations the clinical and prognostic relevance of myeloid mutations, both at the time of treatment failure and perhaps at diagnosis.

Of 31 mutations found in the IPSS-M, an additional four mutations found in familial predisposing conditions (DDX41, GATA2, CHEK2, SAMD9) were searched as was TET2, for a total of 35 mutations. Fifty-four references were identified. Fifty-three references were preclinical/translational in nature, with one case report (WT1).

Eligible patients were divided into 4 cohorts based on transfusion dependence (TD) and treatment with ruxolitinib (RUX). Our analysis identifies unique predictors of response to luspatercept treatment in patients with MF. While the data describe our findings across cohorts, cohort 3B (TD, receiving RUX), which had the highest response rate, also had higher levels of RANTES and TPO at baseline in responders. The ongoing phase 3 study, INDEPENDENCE (NCT04717414), would validate these observations in a larger cohort of patients