bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon-Gamma Production By Dysplastic Cells Supports an Immune-Tolerant Bone Marrow Microenvironment in Myelodysplastic Syndrome Patients
Authors: Ciciarello Marilena , Girotti Francesca , Ocadlikova Darina , Zannoni Letizia , Ardizzoia Federica , Evangelisti Cecilia , Rossi Cesare , Cavo Michele , Curti Antonio 
Published: December 2024

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of haematological malignancies with a poor prognosis and a risk of evolving into acute myeloid leukaemia (AML). Besides intrinsic cellular defects, extrinsic microenvironmental factors, particularly inflammatory signals in the bone marrow (BM), play a crucial role in MDS progression.
In AML, we demonstrated that leukemic cells produced interferon (IFN)γ, allowing us to stratify them in INFGhigh and IFNGlow samples. Higher IFNγ levels remodelled the BM microenvironment, favouring the indoleamine 2,3-dioxygenase (IDO)1-dependent induction of immunosuppressive Tregs associated with increased engraftment of leukemic cells in a mouse model. Furthermore, AML samples with increased IFNγ production showed downregulated expression of HLA class II genes, including CIITA (Class II major histocompatibility complex transactivator). Since leukemic cells with high CIITA methylation are resistant to HLA-dependent IFNγ up-regulation, CIITA methylation/HLA-downregulation could represent a further IFNγ-dependent mechanism of immune suppression. This study aims to explore Tregs induction and HLA down-regulation as putative IFNγ-dependent mechanisms of tolerance and immune escape in MDS, eventually favouring AML progression.
Methods: We used quantitative real-time PCR and flow cytometry to characterize BM-derived MDS samples (N=22) at diagnosis.
Results: MDS samples showed varying IFNγ levels, generally higher than in AML samples. MDS samples had more IFNγ-positive cells in the BM than IFNGlow AML samples, with dysplastic cells being the primary source of IFNγ, although CD3+, CD8+ T cells, and NK cells also contributed. Interestingly, we found a positive correlation between IFNγ and IDO1 expression at both mRNA and protein levels, suggesting an immune-tolerant microenvironment in MDS similar to AML.
Next, MDS samples had a higher percentage of total Tregs than healthy donors and IFNGlow AML samples but lower than INFGhigh AML samples. Treg levels varied with MDS prognostic risk. MDS samples also exhibited different levels and patterns of HLA class II gene expression correlated with IFNγ, with some MDS samples holding an IFNγ-inducible HLA class II gene expression and others with a not-inducible HLA class II gene expression, suggesting a correlation with CIITA methylation grade.
Summary/Conclusions:
This study shows that IFNγ production by MDS cells remodels the BM landscape toward IDO1 upregulation, Treg induction and modulation of HLA class II gene expression, supporting the immune-tolerant role of inflammation, which is emerging as a critical aspect in AML prognosis and outcome and could be implied in MDS risk stratification and progression in AML.
The Combination of the Novel Trifunctional BCMA NK Cell Engager SAR445514 with IMiDs and Celmods Enhances Cytotoxicity Against Multiple Myeloma Cells As Compared to Single Agents
Authors: Tang Alexandre , Zaghi Elisa , Perlat Elodie , Boisrobert-D'heilly Virginie , Van de Velde Helgi , Desjonqueres Alexandre , Fantin Valeria , Chiron Marielle , Virone-Oddos Angela 
Published: December 2024

Introduction:
SAR445514 (SAR'514) is a trifunctional anti-BCMA NK Cell Engager (NKCE), currently in a phase 1/2 trial in patients with relapsed/refractory (R/R) multiple myeloma (MM) (NCT05839626). SAR'514 acts by targeting BCMA antigen expressed on MM cells and by co-engaging NKp46 and CD16a activating receptors on NK cells, facilitating the formation of an immunological synapse between NK and BCMA-positive tumor cells. This leads to NK cell activation, degranulation and tumor cell killing. The anti-tumor activity of SAR'514 in preclinical models has been previously described (Tang et al. “The novel trifunctional anti-BCMA NK cell engager SAR'514 has potent in-vitro, in-vivo and ex-vivo anti-myeloma effect through dual NK cell engagement” American Association for Cancer Research 2023). Herein, we further document SAR'514 in vitro anti-myeloma effects in combination with pomalidomide (IMiD), iberdomide and mezigdomide (CELMoDs), which have established or emerging therapeutic roles in MM.
Methods:
The cytotoxic activity of SAR'514 was evaluated in vitro as a single agent alongside pomalidomide, iberdomide or mezigdomide and also as a combination with each of these IMiD/CELMoDs against the fluorescent BCMA-positive H929-RFP MM cells, in the presence of healthy donor NK cells at an effector to target ratio set at 1:2 during 4 days by live-cell imaging analysis (Incucyte system).
Results:
SAR'514 and the different IMiD/CELMoDs demonstrated potent MM cell killing in a concentration-dependent manner as single agents against H929 cells as compared to an isotype control that does not bind to BCMA. When SAR'514 was combined with either pomalidomide, iberdomide or mezigdomide, a higher cytotoxic activity was observed as compared to single agent pomalidomide (p=0.1197) and significantly higher as compared to single agent iberdomide (p=0.0035) or mezigdomide (p=0.0026). SAR'514 shows the highest potency in combination with mezigdomide.
Conclusion:
In summary, these results demonstrate that the combinations of SAR'514 with pomalidomide IMiD or iberdomide and mezigdomide CELMoDs potentiate MM tumor cell killing in vitro and provide consistent support for the evaluation of this combination in patients with multiple myeloma.
Shock Index As a Predictor of Earlier Risk of Vaso-Occlusive Crisis in Trauma Patients with Sickle Cell Disease
Authors: Parchuri Ektha , Ashraf Rida , Owais Aqsa , Lapping-Carr Gabrielle , Brown Joshua B 
Published: December 2024

Objectives: Clinical implications and management of traumatic injury in individuals with sickle cell disease (SCD) are poorly understood. Trauma exposure may increase post-injury vaso-occlusion, potentially causing secondary complications. The shock index (SI), calculated as the heart rate divided by systolic blood pressure at emergency department (ED) admission, represents the degree of shock after injury. Values of the SI &gt;0.9 are associated with the need for massive transfusion, emergency surgery, and increased mortality in the setting of trauma. We evaluate the shock index (SI) as a predictive tool for prognosis, examining its association with vaso-occlusive events (VOE) in trauma patients with SCD.
Methods: In this retrospective cohort study, medical records of adult patients with SCD with an emergency department (ED) visit for traumatic injury from 2000-2022 were reviewed. The primary exposure was the SI. Our primary outcome was time-to-VOE. Cox regression determined the association between time-to-VOE and SI, adjusting for demographic data (age, gender), mechanism of injury, trauma team activation (TTA), hemoglobin and hematocrit at time of admission.
Results: Records of 356 adult SCD patients were reviewed; 54 patients had an ED visit for traumatic injury with measures for SI, hemoglobin, and hematocrit at time of admission. The cohort had a mean age of 31.83 years with male predominance (66.1%). Mean hemoglobin, hematocrit, and SI at admission were 10.80, 31.79, and 0.71 respectively. Mean time-to-VOE was 3.52 days. Cox proportional hazards model revealed that SI (HR = 14.63 (95% CI: 1.40-152.70), P = 0.025) particularly at a critical threshold of 0.79, and TTA (HR = 0.37, P = 0.03), were significantly associated with increased hazard of earlier time-to-VOE. Injury hematocrit and hemoglobin, SCD genotype, age, and gender did not exhibit statistically significant associations with time-to-VOE.
Conclusion: Patients with SCD with a higher SI value are expected to have a significantly earlier time-to-VOE than patients with lower SI, especially at a critical threshold above 0.79. Our results are consistent with prior data supporting the need for trauma team activation to provide critical interventions in patients with SCD following trauma. Future research may refine risk assessment models to anticipate disease-specific complications and allow tailored interventions in sickle cell patients following trauma.
Auto-HSCT Vs CAR-T Cell Therapy for Paients with Relapsed/Refractory DLBCL in Partial Remission with Deauville Score of 4 or 5 after Salvage Chemotherapy
Authors: Chen Siyuan , Wang Li , Xu Pengpeng , Cheng Shu , Tang Wei , Wu Wen , Ji Mengmeng , Zheng Zhong , Yan Zixun , Sheng Lingshuang , Shen Yige , Zhao Weili 
Published: December 2024

Introduction: For patients with diffuse large B-cell lymphoma (DLBCL) who achieve partial remission (PR) after salvage chemotherapy, the comparative difference in efficacy between autologous stem cell transplantation (auto-HSCT) and chimeric antigen receptor T-cell (CAR-T) therapy remains unclear. The aim of this study is to evaluate the relative efficacy of auto-HSCT vs CAR-T cell therapy in the retrospective cohort of patients with relapsed/refractory DLBCL who achieve partial remission (PR) with Deauville Score of 4 or 5 after salvage chemotherapy, and to provide evidence for treatment options of this population.
Methods: In a single center retrospective cohort, 35 adult patients (age≥18 years) with relapsed/refractory DLBCL who received auto-HSCT (2021-2024, n=16) or CAR-T cell therapy (2018-2024, n=19) in PR status with Deauville Score of 4 or 5 by positron emission tomography/computed tomography (PET/CT) after second-line or higher salvage chemotherapy were identified. Relevant clinical factors were assessed and there were no significant differences between the two groups at baseline.
Results: The median follow-up time was 16.1 months (range 0.8-67.8). Of the 16 patients who received auto-HSCT, three experienced disease progression but none died, while in the CAR-T therapy group, five experienced disease progression and three of them died ultimately. There were no significant differences in progression-free survival (PFS) (P=0.588) and overall survival (OS) (P=0.106) between patients in the auto-HSCT group and the CAR-T cell therapy group (2-year PFS: 84.6% vs 65.8%; 2-year OS: 100.0% vs 80.2%). Either in the univariable analysis or in the multivariable regression analysis, Deauville Score and the choice of treatment with auto-HSCT or CAR-T cell therapy was not associated with PFS and OS.
Conclusions: In our study cohort, for relapsed/refractory DLBCL that reached PR after salvage therapy, similar PFS and OS were observed in both cohorts of the auto-HSCT and CAR-T cell therapy, regardless of Deauville score of 4 or 5. Although not statistically different, there was a trend toward better OS in the auto-HSCT group. Considering the cost of CAR-T cell therapy product preparation and the clinical risks associated with cytokine release syndrome (CRS), our results suggest the continued clinical significance of auto-HSCT for the treatment of this group of patients by demonstrating real-world outcomes.
A Single Mutation in the SENP1 Region Regulates the Excessive Erythropoiesis in the Andes
Authors: Azad Priti , Akbari Ali , Zhou Dan , Poulsen Orit , Mali Prashant , Bafna Vineet , Haddad Gabriel 
Published: December 2024

Background: Approximately 20% of individuals living in Peruvian mountains suffer from debilitating Monge's disease or Chronic Mountain Sickness (CMS). They manifest the disease in adulthood and often die because of excessive erythropoiesis (EE) (Hematocrit of &gt;65%, averaging 72%, mostly occurring in males), an extreme phenotype that often leads to myocardial infarction or stroke. The uniqueness of this Andean population is even more significant when we realize that there are individuals who live side by side at the same altitude as those with CMS but do not suffer from the same extreme phenotype (non-CMS). We have shown a critical role of SENP1 (a gene we obtained from differential SNP analysis throughout whole genomes) in regulating EE response in the highlanders. In order to understand the mechanism(s)that upregulates SENP1 levels in CMS, we applied bioinformatics approaches and CRISPR/Cas9-mediated genomic editing to decipher causal SNPs in the SENP1 region.
Methods: We performed Whole Genome Analysis and applied bioinformatics methods iSAFE (integrated Selection of Allele Favored by Evolution) and CADD (Combined Annotation Dependent Depletion) Score to identify causal SNPs in the selected region of SENP1 gene that could lead to the pathology. We further utilized an in-vitro human iPS-derived model system and CRISPR approach to switch alleles and study their functional role in regulating the EE response.
Results: By applying iSAFE and CADD score we were able to shortlist 7 causal SNPs: rs10783232, rs7959755, rs17122612, rs72644843, rs11609399, rs11613781 and rs60629297. Among them, rs7959755 and rs10783232 were the top ranked (Rank 1 and 2) SNPs. We successfully generated and validated A to G switch in the rs10783232 in the non-CMS cells using CRISPR. We further tested the impact of this switch on function of the allele and observed a significant increase in SENP1 mRNA levels (p&lt;0.05) as well doubling of BFU-e colonies (p&lt;0.05) in the non-CMS cells as compared to the control non-CMS cells. We also tested the effect of allele switch (G to A) for the lower ranked (Rank 44) SNP rs11613781 and did not observe a significant effect on SENP1 levels or BFU colony formation.
Conclusion: These results demonstrate that rs10783232 plays a critical role in regulating SENP1 mRNA levels under hypoxia as well as the EE in the Andean highlanders.
Dynamic Changes in Proteostasis Network Activity Influence Hematopoietic Stem Cell Ontogeny and Human Umbilical Cord Blood Fitness
Authors: Yu Helena , Signer Robert 
Published: December 2024

Hematopoietic stem cells (HSCs) establish hematopoiesis and maintain regeneration of blood and immune cells to meet shifting demands for blood cell production during development and throughout life. The protein homeostasis (proteostasis) network is uniquely configured in adult HSCs to preserve stem cell fitness and longevity. However, the regulation of proteostasis in developing HSCs is largely unexplored. Here, we comprehensively analyzed proteostasis network activity throughout fetal and neonatal development. Fetal HSCs exhibited up to 7-fold higher protein synthesis rates than their adult counterparts but contained similarly low amounts of unfolded and misfolded proteins as adult HSCs, which depend on unusually low protein synthesis rates to preserve proteome quality. Surprisingly, this was not accomplished through enhanced protein degradation as fetal and adult HSCs exhibited similarly low protein degradation activity. However, we found that fetal HSCs preferentially activated Heat shock factor 1 (Hsf1), a key proteostasis sensor and master regulator of the heat shock response, and preferentially expressed multiple Hsf1 target genes. Conditional deletion of Hsf1 in the developing hematopoietic system resulted in compensatory suppression of protein synthesis and aberrant expansion of fetal liver HSCs but had no effect when deleted in young adult HSCs. These data indicate that fetal and adult HSCs utilize distinct mechanisms to preserve proteostasis.
Strikingly, as part of these studies, we discovered that HSCs exhibit a dramatic spike in unfolded protein abundance at birth. This raised the question of whether proteostasis disruption limits the efficacy and regenerative potential of human umbilical cord blood-derived hematopoietic stem and progenitor cells, which are collected immediately after birth. To test this, we fractionated umbilical cord blood-derived CD34+ cells based on unfolded protein content and assessed their function. CD34+ cells with low unfolded protein content had up to 9-fold higher colony-forming efficiency than CD34+ cells with high unfolded protein. Furthermore, CD34+ cells with high unfolded protein content exhibited diminished reconstituting activity in xenotransplantation assays in vivo.
These findings indicate that the HSC proteostasis network undergoes dynamic changes throughout ontogeny and that HSCs depend on distinct age-specific mechanisms to maintain proteostasis throughout life. Stratifying CD34+ cells by variations in proteostasis identifies populations with varied fitness and engraftment potential. As a result, uncovering distinct proteostasis dependencies could offer a unique window for uncovering new therapeutic avenues for enhancing HSC fitness that leverage developmental stage-specific proteostasis programs and reveal proteostasis-based biomarkers as predictors of stem cell quality and transplantation outcomes.
Epigenomic Biomarkers for Treatment Resistance & Lineage Switching Potential in Acute Leukemia
Authors: Eiken Alexandria P , Burmeister Liala , Janssens Derek , Triche Timothy J 
Published: December 2024

Acute lymphoblastic leukemia (ALL) is the most common childhood leukemia, and modern induction protocols secure remission in up to 98% of pediatric cases. But relapse rates are high, and late effects are common among survivors. Infant ALL, particularly KMT2A rearranged (KMT2Ar) disease, has poor long-term survival (about 50%) despite decades of treatment optimization.
KMT2A was originally named MLL, for Mixed Lineage Leukemia. Lineage switching via loss of transcriptional and antigenic programs defines an ultra-high-risk group of KMT2Ar ALL. Lineage specific immunotherapy in frontline ALL treatment has fueled increasing reports of lineage switching, spurring a search for markers predictive of switch potential. Relapses of ALL, such as acute myeloid leukemia (AML) or mixed-phenotype leukemia (MPAL), are almost uniformly refractory. Even among primary MPAL patients, KMT2Ar cases have notably unfavorable outcomes.
Menin inhibitors (MENi) target key vulnerabilities of KMT2Ar leukemia. Clinical reports of rapidly developing MENi resistance, often associated with lineage switching, have spawned a search for markers of resistance potential. However, a subset of KMT2Ar AML patients with monocytic features responds durably to CD33-targeted immunotherapy and chemotherapy. This suggests that myeloid transformation potential alone is insufficient to predict treatment outcome. We reasoned that epigenomic profiling of ALL, AML, and MPAL patient samples, before and after lineage switching and MENi resistance, could inform a search for treatment-relevant biomarkers.
In a cohort of 37 KMT2Ar cases profiled via AutoCUT&Tag, we identified an excess of the histone acetylation reader ENL at non-canonical AML-specific targets among lineage-switching ALL cases. ENL was significantly enriched at these sites in patient samples before lineage switching but absent in B-ALL cases that did not switch lineages. Previous work in a small cohort of adult MPAL cases showed significantly better outcomes in (mostly fusion-negative) cases whose AML-like or ALL-like DNA methylation signatures matched the target of therapy.
To investigate whether this observation could extend to KMT2Ar cases and inform MENi resistance, we analyzed DNA methylation across correlated blocks of CpG loci overlapping ENL binding sites in 1599 pediatric and adult ALL, AML, MPAL, and normal bone marrow samples. We found significant differences in DNA methylation between cases with favorable and unfavorable outcomes, particularly in KMT2Ar cases with lineage alterations at relapse, and these differences were more pronounced at noncanonical (lineage-switch-related) AML associated peaks. Our results illustrate the feasibility of rapid epigenomic profiling in high-risk acute leukemia for clinical trial optimization and improvement of outcomes in KMT2Ar cases.
Eltrombopag Plus G-CSF for Peripheral Blood Stem Cell Mobilization: Interim Analysis of a Single Arm, Phase 2 Trial
Authors: Yu Ta-Chuan , Huang Tai-Chung , Wu Shang-Ju 
Published: December 2024

Background
Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard treatment for relapsed/refractory lymphoma. However, 9% of patients in the plerixafor era could still not obtain adequate peripheral blood stem cells (PBSC) for auto-HSCT. Thrombopoietin (TPO) receptor agonists have been shown to stimulate stem cell proliferation. This study aimed to address whether add-on eltrombopag could improve the successful rate of autologous PBSC harvest.
Methods & Materials
In this phase 2, single-arm IIT, East-Asian patients with lymphomas scheduled to receive ESHAP chemo-mobilization for PBSC harvest are enrolled. Subjects receive eltrombopag at a dose of 75 mg daily from day 6 of ESHAP until the end of PBSC harvest. The primary endpoint is the proportion of patients obtaining more than 2.0 x 106/kg CD34+ cells on the first apheresis day. Based on Simon's two-stage design, an interim analysis was performed when 13 patients received the intervention. A total of 46 patients will be enrolled for final analysis.
Results
The interim analysis completed in May 2024, is reported here. The median age was 55 (range 22-72); DLBCL is the most common diagnosis (n=7). Twelve patients (92.3%) obtained more than 2.0 x 106/kg CD34+ cells on the first apheresis day with the add-on eltrombopag. The median CD34+ cells obtained at the first apheresis was 9.34 x 106/kg. Both results were significantly higher than those derived from the historical control data. No significant eltrombopag-related side effect was observed.
Conclusions
This interim analysis showed that adding eltrombopag to stem cell mobilization is safe and can potentially increase the amount of harvested PBSC. The efficacy and safety will be verified in the final analyses.