TET2 mutation

We prioritized several transcription factors and signaling pathways, which are responsible for P hc alterations. In silico perturbation suggests knocking out EGR regulons or pathways of IL-1R1 and β-adrenoreceptor partially reverses P hc promoted by Tet2 mutation and inflammation.

Additionally, clonal hematopoiesis was associated with increased thrombotic risk (26% vs 8% in NGS-negative cases, p=0.01), independently from TPO-RA exposure, though with an age effect. These data demonstrated the prevalence of clonal hematopoiesis in 18% of adult ITP patients, being associated with older age, relapsed/refractory disease, and high risk of thrombotic complications.

Our findings suggest the addition of HHT to VA might enhance response and mitigate the negative impact of certain genetic patterns in RR-AML while being well tolerated.

The involvement of age-induced genetic/epigenetic alterations in BM niche cells and immunological stressors in hematopoiesis is crucial for understanding the development of age-related hematological malignancies. This comprehensive review provides new insights into the complex interplay between niche cells and HSCs, emphasizing the potential for novel therapeutic approaches that target niche cell functionality and resilience to improve hematopoietic outcomes in the context of aging and metabolic disorders.

Our single center analysis confirmed AITL as the most common variant of nTFHL. AITL and non-AITL appear similar regarding clinical presentation, molecular profile, and outcomes. DNMT3A adversely impact outcomes, as previously reported.

For patients with a probability score < 45%, a bone marrow study may not be needed, with a recommended follow-up every 6–12 months. This comprehensive analysis provides a useful and non-invasive predictive model that enhances diagnostic accuracy which potentially reduces unnecessary procedures.

DTA mutations detected with a clinically used NGS panel in patients with MPN are associated with increased risk of bleeding complications, as well as increased thrombotic risk in a subgroup of patients. These findings support the incorporation of molecular panel analyses in thrombosis and bleeding risk assessment in MPN, and merit further investigation.

Only two patients in the MRD negative group received the FLT3 inhibitor midostaurin combined with chemotherapy...NGS-MRD was not prognostic in this cohort of FLT3-TKD mutated AML patients. Shared first authors: Isabell Arnhardt, Christian M Vonk Shared senior authorship: Michael Heuser, Peter J.M. Valk

Serial NGS-based studies in patients with TP53MT inform important clues to prognosis. While being a dominant or persistent TP53MT clone either at the same configuration or up-trending clonal burden post treatment equates to poor prognosis, it is crucial to study further those who display better clinical outcomes with standard-of-care treatment. Such information will be invaluable for making treatment decisions in this grave prognostic disease otherwise.

According to early findings, NGS panels are extremely effective instruments that provide an entirely new viewpoint on the disease for particular individuals. Future prognostications will depend more on NGS because those who exhibit normal cytogenetics may additionally have gene mutations.

Our findings contribute to a comprehensive characterization of NPM1-mutated AML, enhancing diagnostic accuracy and aiding in the detailed classification of the disease. This information may potentially guide targeted therapies or differentiation-based treatment strategies.

(b) As ICB-exposed patients continue to live longer, the myeloid clonal expansion may portend an increased risk for subsequent myeloid malignancy development. Until now, the selective pressure of ICB/T-cell activating therapies on hematopoietic stem cells were less known and we report preliminary evidence of clonal expansion in epigenetic modifier genes (also referred to as inflammatory CH genes).

In addition, the recently developed molecular taxonomy of MDS will likely facilitate the implementation of precision medicine approaches for these disorders. This will necessitate the establishment of specialized infrastructures within public health systems, involving close collaboration between healthcare institutions, academia, and the life sciences industry.

Current therapeutic strategies include JAK inhibitors like Ruxolitinib, which target the JAK-STAT pathway, alongside supportive treatments such as blood transfusions, erythropoiesis-stimulating agents and developing combinatorial approaches...Recently approved JAK inhibitors, including Fedratinib, Pacritinib, and Momelotinib, have expanded the therapeutic landscape...These technologies elucidate the role of the spleen in MF, highlighting its transformation into a site of abnormal hematopoietic activity, fibrotic changes, and immune cell infiltration, functioning as a "tumor surrogate." By profiling diverse cell populations and molecular alterations within the BM and spleen, SRT facilitates a deeper understanding of MF pathophysiology, helping identify novel therapeutic targets and biomarkers. Ultimately, integrating spatial transcriptomics into MF research promises to enhance diagnostic precision and therapeutic innovation, addressing the multifaceted challenges of this disease.

Chronic inflammation also drives metabolic reprogramming and immune system deregulation, further promoting the expansion of malignant clones. This review underscores the urgent need to fully elucidate the role of inflammation in MDS initiation and highlights the potential of the therapeutical targeting of inflammatory pathways as an early intervention in MDS.

There was no significant difference in event-free survival (EFS) or overall survival (OS) between the patients with and without CH-mutations at CMR or between the patients without allogeneic hematopoietic stem cell transplantation (allo-HSCT) of the two groups. In conclusion, our results suggested that CH-mutations probably did not have prognostic significance in patients with NPM1c AML who achieved CMR, and may be inappropriately for MRD monitoring.

We find that Tet2 -mutant macrophages selectively infiltrate mouse Braf V600E -mutant ATC and that their overexpression of Tgfβ-family ligands mediates resistance to BRAF/MEK inhibition. Importantly, inhibition of Tgfβ signaling restores sensitivity to MAPK pathway inhibition, opening a path for synergistic strategies to improve outcomes of patients with ATCs and concurrent CH.

These findings suggest that the symbiotic relationship between these two cell types could represent a therapeutic vulnerability. This review examines the key components and signaling mechanisms involved in the synapses between B cells and Tfh cells, emphasizing their significant role in the pathobiology of AITL and potential as therapeutic targets.

This unique system allowed the authors to identify a link between IDH2 and TET2 CH mutations, histone demethylases, and altered cytokine signaling, which enabled targeting by ruxolitinib leading to the elimination of CH clones, offering a possible path for preventing the development of malignancy. See related article by Waarts et al., p. 1860.

TET2-mutant human leukaemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocking proliferation of TET2-mutant leukaemic cells and largely reversing the haematopoiesis defects caused by Tet2 loss in mouse models. Together, our findings reveal a chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.

In glutamine-deficient medium, the mRNA expression of glutamine synthetase is increased, which could be related to glutamine addiction in cells. In addition, low-glutamyl medium increased the P-AMPKα protein level in TET2-knockdown HL-60 cells.

P2, N=31, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | Trial completion date: Feb 2026 --> Nov 2024 | Trial primary completion date: Feb 2026 --> Oct 2024

In summary, MDS with NK showed distinct mutation features from those with AK. High-frequency gene mutations together with the mutational evolution suggested the diagnostic and monitoring significance of next generation sequencing for NK-MDS.

Furthermore, we noted an increased percentage of CMML CD34+ stem and progenitor cells expressing CD116 and CD131 in all CBL mutant cases and increased CD116 receptor density compared to healthy controls, similar to CMML overall. In summary, our data demonstrate that CBL mutations are associated with distinct molecular and clinical features in CMML and are potentially targetable with CD116-directed immunotherapy.

Transformation of EBV positive PCMZL appears to be a poor prognostic indicator, with our reported case being the first well defined case transformed to PBL, suspected to arise from myeloid-CH.

A targeted DNA sequencing panel captured common CH mutations in pretreatment blood samples from 957 patients enrolled in Alliance A031201: a randomized trial of enzalutamide ± abiraterone/prednisone in the first-line mCRPC setting. H-CH and TET2-mutated CH were associated with more CVAEs. These findings inform the risk/benefit discussion about ARPIs in mCRPC.

DTA mutations are frequently observed in patients with MDS, often accompanied by genes involved in RNA splicing and transcription factors like SF3B1 and RUNX1. DTA and concomitant mutations affect prognosis in MDS patients and RUNX1 was identified as an independent poor prognostic factor in patients with DTA mutations.

This study reveals how age-associated somatic mutations in the microenvironment may be driving DCC reactivation and relapse. These findings may provide a new genetic biomarker of relapse and inform CH-targeted trials to improve breast cancer patient outcomes.

Thus, early CH-associated mutations that precede malignant transformation subsequently shape the evolutionary trajectories of AML through diagnosis, therapy, and relapse. DNMT3A , TET2 and ASXL1 mutations persist through AML-directed therapy Distinct CH-related mutations shape the evolutionary trajectories of AML from diagnosis through relapse.

No distinct associations were observed with iRBD. PD is linked to increased odds of CHIP with TET2 mutations, suggesting immune dysregulation in PD pathophysiology.

We present seven cases of ALK+ LBCL, discussing the correlation between fusion genes and ALK protein expression, and enhancing our understanding of the genetic attributes of this tumour. This study also shows the loss of 5hmC in nearly all seven ALK+ LBCL cases, independently of TET2 mutations.

Patients with CML-BP may have ETP-ALL. These patients usually have an aggressive clinical course, requiring intensive therapy, and may benefit from stem cell transplantation.

STAT3 mutation is present in various MNs, but not in MPN. It is often an early event or occurs upon leukemic transformation, suggesting an important role in the pathogenesis and progression of MNs by activating JAK-STAT pathway. It may help identify a subset of patients with MNs who may benefit from targeted therapy.

To explore the broader effects of IP-10 loss, we crossed IP-10-/- mice into a series of MPN mouse models and show that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together these data point to a potential role for blocking IP-10 activity in the management of MPNs.

Post-CAR-T MN is associated with extremely poor prognosis and any potential pathophysiological link withCAR-T therapy is poorly understood. The emergence of post-CAR-T MN in our patient cohort is likely to bemultifactorial. Patients were older and heavily pre-treated, and the majority had HThigh scores, which ispredictive of haematological toxicity, but has not to date been associated with MN (6).

Aims: Here, we report a comprehensive analysis of baseline M-CHIP mutational landscape in pts enrolled in theFondazione Italiana Linfomi (FIL) MCL0208 phase 3 trial (NCT 02354313), evaluating lenalidomide (LEN)maintenance vs observation after chemoimmunotherapy and ASCT in untreated MCL pts ≤ 65 years... In conclusion, we provided the M-CHIP mutational landscape at baseline in younger MCL pts from aprospective clinical trial and we showed for the first time the unfavorable clinical impact of large CH clones onMCL progression. Further studies are ongoing on CH mutations detected during follow-up.

NPM1 mutations were identified in 21. 7% of 1,520 patients. Patients with NPM1mut were older and had higherWBC counts and LDH levels, and more often had a normal karyotype, but less adverse cytogenetic features,including monosomal karyotype and MR cytogenetic abnormalities at diagnosis compared to NPM1wtpatients.

The cumulative incidence of at least one reported malignancy was lower for patients with TET2 mutations treated with canakinumab vs those treated with placebo. These findings support a potential role for canakinumab in cancer prevention and provide evidence of IL-1β blockade cooperating with CH mutations to modify the disease course.

ddPCR-MRD is a feasible approach to predict relapse after allo-HSCT in AML/MDS patients with non-DTA genes and is more accurate when combined with MFC.

Retrospective clinical review where possible showed that 83% (28/34) UBA1-mutant cases had VEXAS-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1-mutations in MDS patients argues for systematic screening for UBA1 in the management of MDS.

Moreover, we observed a tendency of CHIP-positive patients to achieve a suboptimal response to therapy compared to those without. A sub-clone dynamic of high-fitness mutations over time was confirmed.

MPN-BP and AML-MR harbor similar somatic mutations and clinical outcomes, suggesting a unified clinical disease entity.