HemaSphere最新文献

Studying how microenvironmental cues influence metabolic reprogramming can uncover mechanisms driving tumor progression. Using an in vitro model with proliferative stimuli of the in vivo lymph node niche (LN)—including interleukin-21 (IL-21)—we examined metabolic rewiring in chronic lymphocytic leukemia (CLL) cells. We found that the metabolic intermediates of upper glycolysis and its branching pathways are key in fulfilling metabolic demands of proliferating CLL cells. Among branching pathways, the pentose phosphate pathway (PPP) was the most transcriptionally upregulated in proliferating CLL cells. Increased expression of PPP genes was detected ex vivo at the bulk and single-cell level in the LN-resident and -emigrating CLL cells, with more consistency across enzymes of the nonoxidative PPP branch. Expression of the latter correlated with shorter failure-free survival in CLL patients. At the cellular level, metabolomics and 13C-glucose tracing confirmed high activity of the non-oxidative PPP in proliferating CLL cells. IL-21 regulated the expression of PPP enzymes, with STAT3 serving as the primary downstream effector. CRISPR/Cas9-mediated silencing of PPP enzymes revealed that, in vitro, proliferating CLL cells from most patients were not dependent on these enzymes. In contrast, silencing transketolase (TKT)—the rate-limiting enzyme of the non-oxidative PPP—abolished tumor engraftment in vivo, demonstrating that CLL cells rely on this pathway within the tumor microenvironment. These findings uncover a CLL-specific metabolic reprogramming wherein IL-21–STAT3 drives PPP activity and identify the nonoxidative PPP as a critical in vivo vulnerability of leukemic cells in the murine CLL model.

Hereditary anemias encompass a genetically heterogeneous spectrum of disorders, often involving multi-locus inheritance, which can complicate clinical management and worsen disease severity. This study investigates the impact of the co-inheritance of SEC23B loss-of-function pathogenic variants, which lead to congenital dyserythropoietic anemia type II (CDA II), and PIEZO1 gain-of-function pathogenic variants, associated with dehydrated hereditary stomatocytosis type I (DHS1), on hematological parameters and iron metabolism. Among 583 patients with suspected hereditary anemia, 13 were found to carry both SEC23B and PIEZO1 variants, leading to a dual diagnosis of CDA II and DHS1. Compared to those with isolated CDA II, these patients exhibited a significantly higher absolute reticulocyte count and bone marrow responsiveness index, alongside an increased prevalence of elevated ferritin levels. Functional studies in Hep3B human hepatoma cells confirmed that SEC23B knockdown combined with PIEZO1 gain-of-function led to marked ferritin accumulation and reduced hepcidin expression, driven by altered BMP/SMAD signaling and ERK1/2 MAPK pathway. These findings demonstrate how multi-locus inheritance can modify disease severity, particularly by exacerbating iron overload. Our results underscore the clinical relevance of comprehensive genetic testing for enhanced risk stratification and personalized management of hereditary anemias.

Pediatric regimens improve outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) patients. End-consolidation (time point 2 [TP2]) minimal residual disease negativity (MRD^neg) is associated with improved survival. In this study, standard consolidation chemotherapy was replaced with blinatumomab to improve TP2 MRD^neg—a key survival surrogate in B-lineage ALL. From 2019 to 2022, 55 patients constituted the intention-to-treat (ITT) cohort, median age 25 (range, 16–39) years. Using a Simon's 2-stage design, blinatumomab replaced standard consolidation chemotherapy cycles with TP2 MRD^neg as the primary endpoint. Blinatumomab was associated with an improved TP2 MRD^neg rate of 70.8% (95% CI, 55.9%–83.0%) versus the null hypothesis of 60% (P = 0.037). When compared to our previous ALL06 study, median time from protocol I commencement to next treatment phase was 84 versus 97 days (P = 0.0001), with 82.7% versus 45.1% (P < 0.0001), commencing protocol M or high-risk block therapy by day 94. Induction mortality was 1.8%. Blinatumomab was well tolerated. Median follow-up was 42.9 (range, 1.9–54.7) months, with 3-year disease-free survival (DFS) 88.6% (95% CI, 76.3%–94.7%) and 3-year overall survival (OS) 90.5% (95% CI, 78.6%–95.9%) in the ITT cohort. Higher than medium-risk patients had poorer DFS but not OS. Standard genomic risk patients had 100% 3-year DFS and OS. Adverse genomic risk stratified by TP2 MRD^pos predicted poorer DFS but not OS. Blinatumomab consolidation for de novo B-lineage AYA ALL was associated with high MRD^neg rates and excellent survival, particularly in standard-risk disease. Genomics may assist in predicting response to blinatumomab in de novo ALL (ACTRN12618001734257).

Erythropoiesis is a finely regulated process ensuring continuous red blood cell production to maintain oxygen delivery. Disruptions in this process give rise to defective erythropoiesis, characterized by impaired lineage commitment and progenitor development, and ineffective erythropoiesis (IE), marked by expansion of erythroid progenitors with intramedullary apoptosis of late precursors. These abnormalities underlie anemia in diverse hematological disorders, including β-thalassemia, sickle cell disease (SCD), myelodysplastic syndromes (MDSs), and emerging entities such as vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS). This review synthesizes recent insights into the molecular regulators of erythropoiesis, emphasizing the roles of GATA1, its chaperone HSP70, caspase activity, and extrinsic signals such as growth differentiation factor 11 (GDF11) and inflammatory cytokines. We highlight how globin-chain imbalance, inflammasome activation, oxidative stress, and clonal mutations converge on common pathways that disrupt erythroid maturation. Advances in therapy now directly target these mechanisms: Luspatercept, a TGF-β ligand trap, has transformed care in β-thalassemia and MDS by restoring late-stage differentiation, while anti-inflammatory strategies, metabolic modulators, and gene editing approaches are being actively explored. Together, these discoveries reframe IE as a modifiable process rather than an inevitable consequence of disease. By distinguishing defective from IE and mapping their mechanistic underpinnings, this review outlines how novel therapeutic strategies can improve anemia, reduce systemic complications, and ultimately enhance outcomes in patients with erythroid disorders.

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for high-risk childhood leukemia but may lead to chronic graft-versus-host disease (cGvHD), a severe long-term complication. This study analyzed data from the LEA cohort, including 446 childhood leukemia survivors treated with allogeneic HSCT. The standardized cGvHD evaluation, using the NIH consensus criteria, was conducted 8.7 ± 0.3 years post-HSCT. Long-term cGvHD was reported in 21% of patients (9% mild, 7% moderate, 5% severe), primarily affecting eyes, skin, lungs, and mouth, with some cases involving multiple organs. Most patients with long-term cGvHD were untreated (84%), while 11% received systemic and 5% local treatments. cGvHD was associated with other long-term complications. Administration of anti-thymocyte globulin was a significant determinant (OR 0.6, 95% CI 0.4–0.99, P = 0.045). Long-term cGvHD showed a marked detrimental effect on the quality of life (QoL), even after adjusting for the other long-term complications. The SF-36 physical and psychological adjusted composite scores in patients with versus without cGvHD were 50 ± 2 versus 55 ± 1 (P = 0.01) and 38 ± 2 versus 43 ± 1 (P = 0.01), respectively. Even mild and moderate forms significantly affected the QoL, especially on psychological dimensions. These findings support standardized cGvHD evaluation and management to improve long-term outcomes of transplanted childhood leukemia survivors.

Diamond–Blackfan anemia (DBA) is a rare bone marrow failure syndrome accompanied by cardiovascular, skeletal, and urogenital abnormalities. Most of the affected individuals carry mutations in ribosomal proteins, including RPS19, a component of the 40S ribosomal subunit. We developed a transgenic Rps19 mouse model harboring a deletion of conserved R67 that displays a variable phenotype ranging from mild hematopoietic defects to severe anemia and a set of other skeletal, muscular, and cardiac abnormalities with shorter survival. This mouse model exhibited an activation of the p53 signaling pathway in red blood cell committed hematopoietic stem and progenitor cells, affecting erythroid lineage development. Competitive transplantation assays using Rps19^R67∆ bone marrow progenitor cells confirmed that short-term repopulating hematopoietic stem cells (HSCs) and their progenitor lineages were affected, while their differentiation was rescued after deletion of the tumor suppressor Trp53. Rps19^R67∆ mutation leads to pre-ribosomal RNA (pre-rRNA) accumulation coupled with activation of p53, even at relatively immature hematopoietic stages. In conclusion, we present a mouse model that represents a powerful tool for exploring new therapeutic options for the treatment of ribosomal disorders, including DBA.

Standard frontline treatment of chronic lymphocytic leukemia (CLL) is with fixed-duration venetoclax-based doublets or indefinite covalent Bruton tyrosine kinase inhibitor (BTKI). Although these approaches achieve excellent results, venetoclax doublets have diminished efficacy in high-risk biological subgroups, and indefinite covalent Bruton tyrosine kinase inhibitor (cBTKI) is associated with cumulative cardiovascular and infectious toxicity. Triplet regimens for treatment of CLL involve simultaneous use of cBTKI, venetoclax, and anti-CD20 monoclonal antibody. Three major frontline Phase 3 trials (CLL-13/GAIA, AMPLIFY, and A041702) have demonstrated higher rates of undetectable minimal residual disease (uMRD) and longer remissions with triplets than doublets, particularly in patients with IGHV-unmutated (IGHV-U) disease. However, this comes at the cost of increased infectious toxicity, particularly with COVID-19, and thus has translated into a variable impact on progression-free survival (PFS) and, to-date, no overall survival (OS) benefit. Although there are promising Phase 2 data for triplets in patients with TP53 aberrant or relapsed disease, the heterogeneity of treatment duration/MRD definition, lack of control arm, and potential increased toxicity make it premature to use triplets in these groups. We recommend considering triplets in treatment naïve CLL patients with IGHV-U, TP53 wild type, anticipated low incidence/good tolerance of Gr ≥ 3 infection (<70 years old, no major comorbidity and fully immunized) who are well informed and prioritize maximal time off therapy at the expense of increased short-term logistical complexity. Future triplet research should focus on randomized trials in specific genomic subgroups, incorporating novel agents (e.g., non-covalent BTKI, BTK degrader, and next-generation BCL2 inhibitors) and new ways of adapting treatment duration to maximize efficacy and minimize toxicity.

Large B-cell lymphoma (LBCL) with IRF4 rearrangement (LBCL-IRF4-R) is a rare subtype predominantly diagnosed in children and young adults. Whether adult LBCL cases with IRF4 rearrangement (IRF4-R) should be classified as LBCL-IRF4-R remains unclear. Clinicopathological and molecular features of 61 adult LBCL cases with IRF4-R were analyzed and compared to diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), to assess biological heterogeneity. The 61 cases grouped by patient age and site were classified as follows: Group 1 included 13 patients aged ≤40 years, whose features supported LBCL-IRF4-R, showing favorable outcomes with high frequencies of IGH::IRF4 fusion and IRF4 mutations. Group 2 comprised 37 patients aged >40 years with tumors at usual sites; 17 early-stage cases largely retained LBCL-IRF4-R characteristics, whereas three other early-stage cases showed molecular or clinical features more consistent with DLBCL, NOS with IRF4-R. Twelve advanced-stage cases showed aggressive behavior with adverse DLBCL, NOS-associated mutations (e.g., TP53), suggesting classification as follicular lymphoma grade 3A (FL-3A) and DLBCL with IRF4-R or DLBCL, NOS with IRF4-R. Five cases lacked sufficient data for definitive classification. Group 3 included 11 patients aged >40 years with tumors at unusual extranodal sites; except for one case classified as LBCL-IRF4-R, the remaining 10 cases showed aggressive clinical behavior with frequent MYD88 mutations, favoring classification as FL-3A and DLBCL with IRF4-R or DLBCL, NOS with IRF4-R. These findings support a multidimensional approach that integrates age, tumor site, and clinicomolecular features to refine classification, enhance risk stratification, and guide personalized management in adult LBCL cases with IRF4-R.

In AML with 3q26.2 rearrangements (r) the distal GATA2 hematopoietic enhancer becomes aberrantly relocated leading to activation of EVI1 expression. EVI1 is a transcriptional regulator that plays a role in proliferation and maintenance of a stem cell-like phenotype in AML. BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive ATPases of the BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. They regulate access to enhancers/promoters and gene-expressions orchestrating AML stem/progenitor cell proliferation and differentiation. AML with 3q26.2 rearrangements are clinically challenging and prognosis remains very poor. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induced differentiation and lethality in AML cells with MECOM-r, perturbed chromatin accessibility and depleted expression of EVI1, c-Myc, CD44 and CDK4. Co-treatment with FHD-286 and decitabine, BET inhibitor (BETi) or HAT inhibitor synergistically induced in vitro lethality in patient-derived AML cells with MECOM-r. In patient-derived xenograft (PDX) models of AML with MECOM-r, compared to each drug alone, co-treatment with FHD-286 and BETi OTX015 significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with chromosome 3q26.2 rearrangement and EVI1 overexpression.