Blood advances最新文献

Abstract: Low bone mineral density (BMD) is a prevalent skeletal finding in sickle cell disease (SCD), but its clinical consequences are poorly understood. We hypothesized that low BMD, independent of osteonecrosis (ON), would associate with pain in adults with SCD. In the SCD Bone Pain study, 53 ambulatory adults (64% females; mean age, 38 ± 11 years; 66% hemoglobin [Hb] SS/Sβ0 thalassemia) underwent dual-energy X-ray absorptiometry scans of their lumbar spine, hip, forearm, and whole body. They also completed the Adult Sickle Cell Quality of Life Measurement Information System pain impact questionnaire. Twenty-three participants (43%) had low BMD, defined as lumbar spine, total hip, or femoral neck BMD z scores of -2 or less. In multivariate linear regression, lumbar spine BMD z scores significantly changed by +0.31, -0.29, -0.14, and -1.3 for every unit increase in Hb, indirect bilirubin, and white blood cell count, and with crizanlizumab use, respectively. Pain impact T-scores significantly decreased (worsened) by 6.0 and 6.5 with reduced estimated glomerular filtration rate and chronic opioid therapy but increased (improved) by 3.8 for every unit increase in serum phosphate. The median [interquartile range] pain impact T-scores were significantly lower in participants with low BMD and ON (38.3 [37.4, 40.1]) than those with either low BMD (49.5 [43.6, 54.4]; P = 3 × 10-5) or ON (52.7 [45.3, 57]; P = 2 × 10-4) alone. Whether sickle cell-related low BMD results from impaired bone formation and/or accelerated bone loss remains unclear. Understanding how low bone density, with or without ON, mediates SCD pain warrants further investigation. This trial was registered at www.clinicaltrials.gov as #NCT05283148.

Abstract: Hematopoiesis changes over the lifetime to adapt to the physiology of development, maturation, and aging. Temporal changes in hematopoiesis parallel age-dependent incidences of certain blood diseases. Several heterochronic regulators of hematopoiesis have been identified, but how the master transcription factor (TF) circuitry of definitive hematopoietic stem cells (HSCs) adapts to changes in physiology over the life span remains unknown. In this study, we show that programmed upregulation of expression of the erythroblast transformation-specific family TF Erg from prenatal to adult maturation is evolutionarily conserved and required for implementation of adult patterns of HSC self-renewal and myeloid, erythroid, and lymphoid differentiation. Erg deficiency maintains fetal transcriptional and epigenetic programs in adulthood, and persistent juvenile phenotypes in Erg haploinsufficient mice are at least in part dependent on deregulation of the fetal-biased factor Hmga2. Overall, we identify a mechanism whereby master HSC TF networks are rewired to specify stage-specific hematopoiesis, a finding directly relevant to age-biased blood diseases.

Abstract: Metabolic reprogramming is a hallmark of cancer and is essential for sustaining leukemogenesis. In acute myeloid leukemia (AML), a high dependency on oxidative phosphorylation (OXPHOS) is often linked to poor outcomes, and its inhibition has shown to be highly effective. However, most OXPHOS inhibitors are not clinically translatable because of significant side effects. Thus, repurposing safe US Food and Drug Administration-approved drugs that can target OXPHOS is of great interest. Here, we evaluated metformin, an antidiabetic drug that inhibits OXPHOS, in a genetically diverse panel of primary AML samples to identify metabolic profiles that can be used to predict treatment susceptibility. Using label-free quantitative proteome analysis on sorted CD34+/CD117+ AML cells, we performed single-sample gene set enrichment analysis focused on metabolic terms and correlated enrichment scores with metformin sensitivity, followed by functional studies. Ex vivo treatment of AML samples with metformin showed a significant increase in reactive oxygen species levels and ferroptosis induction, especially in samples with disturbed lipid metabolism, such as IDH2- and FLT3-mutant AMLs. In IDH2-mutant cells, cotreatment with palmitate, a saturated fatty acid (FA), increased metformin sensitivity, which could be rescued by CD36 knockdown, rendering these cells more resistant to treatment. Lipidomic analysis revealed profound alterations upon metformin treatment, including increased production of triglycerides and polyunsaturated FAs, further supporting a metabolic shift. We observed upregulation of genes related to lipid droplet formation, including DGAT1, a key enzyme in this process. DGAT1 inhibition was strongly synergistic with metformin, whereas iron chelators acted antagonistically. Our results underscore the potential of leveraging metabolic vulnerabilities in AML to identify more effective and personalized therapeutic strategies.

Abstract: Chimeric antigen receptor T-cell (CART) therapy has transformed the management of relapsed and refractory large B-cell lymphoma (LBCL), but real-world outcomes data is needed to confirm the benefits seen in clinical trial settings. We performed a multicenter retrospective analysis evaluating CART therapy outcomes according to line of therapy, specifically second line (2L) vs third line (3L) vs fourth line (4L) and beyond (4L+). We included patients who received CD19-directed CART therapy for de novo diffuse LBCL or transformed follicular lymphoma. Overall (N = 466), 21% (n = 98) of patients received CART as 2L, 41% (n = 192) as 3L, and 38% (n = 176) as 4L+. Median follow-up from CART infusion was 35 months. Overall response rate and complete response rate were similar for 2L vs 3L vs 4L+. From CART infusion, median progression-free survival (mPFS) and median overall survival (mOS) were similar for 2L vs 3L, but shorter in patients receiving CART as 4L+ (mPFS, 11.6 vs 12.7 vs 5.7 months, P< .001; mOS, not reached vs 69.4 vs 21.9 months, P< .001). In patients with double-hit or triple-hit lymphoma (DHL/THL), receiving CART in 2L vs 3L significantly improved 3-year OS (63% [2L] vs 32% [3L], P = .01). Patients with disease that required bridging therapy were also at increased risk of progression or death. Overall, our findings inform real-world practice wherein CART therapy as 2L vs 3L yields similar survival outcomes in unselected patients. However, patients specifically with DHL/THL should be considered for CART therapy in the 2L outside of the primary refractory disease (PRD) or early relapsed setting.

Abstract: Chronic myelomonocytic leukemia (CMML) is characterized by monocytosis in blood and bone marrow and natural progression to acute myeloid leukemia (AML) in ≤30% of patients. The mutation landscape of CMML has been reported, and animal models that recapitulate its clinicopathologic features and progression are needed. We report a CMML zebrafish model based on transgenic SRSF2P95H expression that closely resembled the human disease. Hematological assessment of the transgenic animals showed myelodysplasia, monocytosis, and leukemia transformation. Transcriptomic analysis confirmed global splicing alterations and identified inflammatory phenotypes associated with activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. DNA damage, R-loop formation, and double-strand DNA accumulation were evident. Inhibition of R-loop formation or cGAS-STING axis significantly reduced gene expression associated with inflammation and immune activation and mitigated the leukemia phenotype. The inflammatory effects and their response to treatment were recapitulated in human hematopoietic stem and progenitor cells. Collectively, our findings show a pathogenetic link between SRSF2P95H and cGAS-STING activation in CMML and its vulnerability to therapeutic intervention.

Abstract: Ineffective erythropoiesis and the resulting anemia are the main characteristics of myelodysplastic syndromes (MDS). Drugs designed to promote erythropoiesis in patients with MDS include erythropoiesis-stimulating agents, such as recombinant human erythropoietin, and transforming growth factor β inhibitors, such as luspatercept, which is approved for the treatment of anemia associated with MDS or β-thalassemia. However, these types of drugs are ineffective in some patients and fail to elicit durable responses in others, underscoring the need for additional therapeutic targets. Here, we sought to define the role of ubiquitin-conjugating enzyme E2O (UBE2O), which remodels the proteome during late erythroid differentiation, in the pathogenesis of ineffective erythropoiesis in the setting of MDS and investigate its potential as a therapeutic target for improving erythropoiesis. UBE2O expression was analyzed in K562 leukemic cells and bone marrow samples from patients with MDS before and after treatment with erythropoietin and luspatercept. Bioinformatic analysis identified a GATA1 binding motif on the UBE2O promoter region, and chromatin immunoprecipitation validated the interaction. Our findings demonstrate that GATA1 binds to the UBE2O promoter, thereby regulating UBE2O transcription and expression. Although further studies are needed to explore the implications of UBE2O in MDS treatment, our work provides potential strategies for novel therapeutic approaches in MDS.