Haematologica最新文献

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Aged hematopoietic stem cells (HSCs) show diminished capacity of self-renewal, skewed lineage output and compromised proteostasis. Ubiquitin proteasomal systems are critical for maintaining protein homeostasis. We show that the levels of Ube2g1, a E2 ubiquitinconjugating enzyme likely involved in clonal selection of HSCs, was elevated in aged murine and human HSCs. We hypothesized that elevated levels of Ube2g1 causally contribute to hematopoietic system aging. Elevated levels of Ube2g1 in young murine HSCs resulted in increased myeloid-to-lymphoid ratio and reduced naïve T-cells, both known hematopoietic aging hallmarks. Interestingly, the ubiquitination function of Ube2g1 didn't primarily account for the observed phenotypes. Elevated levels of Ube2g1 affected global tyrosine phosphorylation, mediated through a Ube2g1-Shp2 axis, which correlated with impaired Tcell development and reduced HSC function. Our work identifies a novel connection between proteins involved in the regulation of ubiquitination and phosphorylation in HSCs that affect phenotypes linked to aging of HSCs.

Clonal hematopoiesis (CH) has emerged as a critical mediator of age-associated diseases, with far-reaching implications for hematologic malignancies, cardiovascular diseases, cancer therapy, autoimmune disorders, and other health conditions. This review synthesizes the current evidence supporting the integration of CH testing and monitoring into clinical practice, with a focus on translating scientific discoveries into actionable diagnostic and therapeutic strategies. We present a systematic framework for establishing and operating a dedicated CH program, drawing on institutional experience and evolving best practices. Our analysis encompasses risk stratification approaches, surveillance protocols, and intervention timing for various CH-associated conditions. Special attention is given to the challenges and opportunities in implementing CH screening within existing clinical workflows, including considerations for genetic counseling, interdisciplinary coordination, and patient education. By providing practical insights and evidence-based recommendations, this review aims to serve as a roadmap for healthcare institutions looking to develop comprehensive CH management programs that bridge the gap between molecular discoveries and clinical care delivery.

In thrombosis and haemostasis, coagulation and platelet activation pathways culminate to form solid fibrin clots, which can become vaso-occlusive or prevent excessive bleeding. We report a novel mechanism describing how developing fibrin clots prolong and modulate the reactivity of thrombin, an enzyme propagating platelet and coagulation activation and forming fibrin from fibrinogen. Using immunological and genetic approaches, we delineate how thrombin bound to the A and Baachains of fibrin E-domains regulates lateral fibrin fibre extension. Our data reveal that fibrin-bound thrombin remains active and is temporarily protected against inactivation by antithrombin-III. Immunological displacement of thrombin from fibrin profoundly lowered its capacity, whereas a peptide mimicking the AA-chain binding-site increased its reactivity. In a cohort of patients with congenital dysfibrinogenemia, carrying FGA, FGB or FGG mutations associated with bleeding or thrombosis phenotypes, we noticed a high thrombin capacity and suppressed thrombinantithrombin-III complex formation, pointing to a prolonged active thrombin lifetime, likely due to abnormal formation of thrombin-containing fibrin. In conclusion, the combination of an impaired clotting and increased thrombogenicity may explain the paradoxical bleeding and thrombotic complications observed in such patients. Development of fibrin-directed agents may offer new therapeutic opportunities to normalize hemostasis or prevent thrombosis.

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The Swedish nationwide study by Leontyeva et al. (Haematologica, sept, 2025) revealed that patients with myeloproliferative neoplasms (MPN) continue to lose life years compared with the general population, with polycythemia vera (PV) showing a 1.8-year loss in restricted mean survival at 15 years. Despite being classified as "low risk," these younger patients lose more life years relative to agematched peers. They face decades of exposure to clonal proliferation, inflammation, and thromboinflammation, which contribute to vascular injury, myelofibrosis, and secondary cancers. Evidence suggests that early, biology-guided therapy may modify this trajectory. Interferon, particularly ropeginterferon alfa-2b, and ruxolitinib reduces JAK2V617F allele burden, systemic inflammation, as reflected by the neutrophil-to-lymphocyte ratio (NLR), and thrombosis rates, demonstrating long-term disease-modifying potential. The challenge lies in identifying which younger patients should receive cytoreductive therapy, as these treatments, while effective, may be poorly tolerated or burdensome over decades. Biological markers such as persistent leukocytosis, elevated NLR, rising JAK2V617F variant allele frequency, or high phlebotomy burden can guide treatment decisions more precisely than age alone. Tailoring therapy in younger PV patients according to disease biology and individual tolerance may prevent irreversible complications, improve quality of life, and ultimately reduce the years of life lost.

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High-dose methotrexate (HDMTX) is a cornerstone of contemporary treatment protocols for both pediatric and adult acute lymphoblastic leukemia (ALL); however, up to 4% of children and 15% of adults develop renal toxicity with severely delayed MTX elimination (DME). Evidencebased guidance on re-exposure after DME is lacking, and omission of further HDMTX may compromise anti-leukemic efficacy and potentially increase the risk of relapse. This study, conducted within the Ponte di Legno international toxicity working group, aimed to evaluate the safety of HDMTX re-challenge in pediatric patients after DME. National investigators from 12 countries provided case-level data on initial DME events and subsequent HDMTX re-exposures via structured questionnaires. Data from 189 patients treated for ALL who experienced DME were analyzed, of whom 143 were subsequently re-exposed to HDMTX. Clinical toxicities after the initial DME included gastrointestinal complications (vomiting, diarrhea, mucositis), infections, and neurological events (encephalopathy, seizures, MTX stroke-like syndrome). Laboratory toxicities comprised cytopenias and hepatic abnormalities. Two patients transiently required dialysis. DME led to chemotherapy modifications in 73% of the patients. After reexposure, toxicities were similar in spectrum, self-limited, and non-fatal. Twenty children (14%) developed recurrent DME, including three with two additional episodes. Recurrent DME could not be predicted by clinical, pharmacokinetic, or demographic variables, nor by uniform MTX dose reduction during re-exposure. In conclusion, re-exposure to HDMTX following DME is feasible and generally well tolerated, although the risk of recurrence is increased. Re-challenge should be considered once renal function has normalized, with careful monitoring and individualized dose adjustment.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), driven by the BCR-ABL1 fusion gene, remains a high-risk malignancy despite therapeutic advances. Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 have significantly improved outcomes, but resistance and relapse persist, necessitating novel strategies such as combining TKIs with bispecific T-cell engagers (BiTEs) like blinatumomab. Blinatumomab redirects T cells to eliminate CD19+ leukemia cells and has shown impressive clinical activity in Ph+ ALL when combined with Src+BCR-ABL1 TKIs. However, this contrasts with preclinical observations reporting that Src kinase inhibition by Src/BCR-ABL1 TKIs antagonizes blinatumomabmediated T-cell activation. Consistent with prior preclinical studies, we demonstrate that dasatinib and ponatinib, unlike SRC sparing TKIs (imatinib, nilotinib), antagonize blinatumomab's T-cell engaging efficacy by potently inhibiting LCK Y394 phosphorylation, a critical step in proximal TCR signaling. This inhibition impairs T-cell proliferation, cytokine production, and NFAT activation. To reconcile this in vitro antagonism with favorable clinical combination outcomes, we confirmed that the mechanism of SRC inhibition is T-cell intrinsic and explored the impact of interleukins. We show that TKI-induced T-cell suppression and antagonism can be significantly improved by supplementing co-cultures with common gamma-chain cytokines, particularly IL-7. IL-7 robustly enhances human T-cell proliferation, reduces exhaustion, and significantly improves blinatumomab's cytotoxic efficacy in the presence of Src/BCRABL1 TKIs.

Clonal hematopoiesis (CH) is defined by the clonal expansion of hematopoietic stem and progenitor cells harboring somatic mutations that confer a fitness advantage. CH is common with advancing age and becomes nearly ubiquitous in middle age. Although typically asymptomatic, CH is associated with an increased risk of hematologic malignancies particularly myeloid neoplasms (MN), diverse non-malignant conditions, and all-cause mortality. Over the past decade, research has provided major insights into the origins of CH. In addition to aging, CH is promoted by environmental exposures, inherited genetic predisposition, and acquired conditions. Large-scale population and longitudinal sequencing studies have identified determinants of clonal behavior. Characterization of the natural history of CH has enabled the development of risk stratification models to identify individuals with CH at high risk for progression to MN, thereby providing a rationale for selecting patient populations best suited for therapeutic intervention trials. Emerging strategies include targeting mutation-specific vulnerabilities, modulating inflammatory pathways, reducing genotoxic therapy-induced clonal selection, and repurposing agents with efficacy in MN. In this review, we summarize current knowledge of the risk factors underlying CH development, highlight recent advances in understanding the determinants of clonal behavior including progression to MN, and discuss emerging therapeutic approaches for preventing malignant transformation and clinical trial design considerations.