Hematopoietic Cell Research Articles

Does size matter? Center-specific characteristics and survival after allogeneic hematopoietic cell transplantation for acute myeloid leukemia: an analysis of the German Registry for Stem Cell Transplantation and Cell Therapy.

We investigated the effect of center-specific variables on overall survival (OS) after allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML). Eligible were adult patients reported to DRST registry receiving first alloHCT for AML from a related or matched (>= 9/10 HLA-match) unrelated donor 2015-2021. Primary endpoint was OS at 12 months from alloHCT. Univariable and multivariable analyses after best subset selection was performed. Of 5328 patients, 83% received alloHCT in a high-volume center (≥40 alloHCT/year); 90% in a university hospital; 90% in a center performing alloHCT for ≥10 years; and 73% in a Joint Accreditation Committee IHCT-Europe and EBMT (JACIE) accredited center. 52% of the patients were in CR1, and ELN risk was adverse in 37% and intermediate in 42%. On multivariable analysis, center-specific factors predicting adverse 12-month OS were program duration.

Differentiating erythroblasts adapt to mechanical stimulation by upregulation of cholesterol biosynthesis via S1P/SREBP-induced HMGCR expression

Understanding how mechanical stress affects erythropoiesis is crucial to produce transfusable erythrocytes in fluid-turbulent bioreactors. We investigated the effects of shear-stress on differentiating CD49d+CD235a+ primary human erythroblasts (EBL) at molecular, cellular, and functional level. Shear-stress, at differentiation onset, enhanced EBL maturation and induced upregulation of genes regulating cholesterol/lipids biosynthesis, causing changes in cell lipid composition. Of note, the osmotic resistance, and the expression of 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the cholesterol biosynthesis pathway, were higher in dynamic cultures. Inhibition of the S1P-induced proteolytic cleavage, activating SREBPs, led to abrogation of HMCGR expression, and loss of EBL in dynamic cultures, similar to lovastatin administration. This data reveals a role for the S1P-SREBP-HMGCR-axis in the regulation of shear-stress induced adaptation during erythropoiesis, shedding light into mechanisms that will assist the upscaling of erythroid differentiation into bioreactors. Moreover, as shear-stress on hematopoietic cells occurs within the bone-marrow, these results introduce a novel signalling axis in the transduction pathways controlling erythropoiesis.

Honing CAR T cells to tackle acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a dismal disease with poor prognosis, particularly in the relapsed/refractory (r/r) setting. Chimeric antigen receptor (CAR) therapy has yielded remarkable clinical results in other leukemias and thus has, in principle, the potential to achieve similar outcomes in r/r AML. Re-directing the approved CD19-specific CAR designs against the myeloid antigens CD33, CD123 or CLEC12A has occasionally yielded morphological leukemia-free states (MLFS) but has so far been marred by threatening myeloablation and early relapses. These safety and efficacy limitations owe in large part to the challenge of identifying suitable target antigens and designing adequate receptors for effective recognition and safe elimination of AML. Building on lessons learned from the initial clinical attempts, a new wave of CAR strategies relying on alternative target antigens and innovative CAR designs is about to enter clinical evaluation. Adapted multi-antigen targeting, logic-gating and emerging cell engineering solutions offer new possibilities to better direct T cell specificity and sensitivity towards AML. Pharmacologic modulation and genetic epitope engineering may extend these approaches by augmenting target expression in AML cells or minimizing target expression in normal hematopoietic cells. On/off switches or CAR T cell depletion may curb excessive or deleterious CAR activity. Investigation of AML-intrinsic resistance and leukemic microenvironmental factors is poised to reveal additional targetable AML vulnerabilities. We summarize here the findings, challenges and new developments of CAR therapy for AML. These illustrate the need to specifically adapt CAR strategies to the complex biology of AML to achieve better therapeutic outcomes.

BRAFV600E induces key features of LCH in iPSCs with cell type-specific phenotypes and drug responses.

Langerhans cell histiocytosis (LCH) is a clonal hematopoietic disorder defined by tumorous lesions containing CD1a+/CD207+ cells. Two severe complications of LCH are systemic hyperinflammation and progressive neurodegeneration. The scarcity of primary samples and lack of appropriate models limit our mechanistic understanding of LCH pathogenesis and affect patient care. We generated a human in vitro model for LCH using induced pluripotent stem cells (iPSCs) harboring the BRAFV600E mutation, the most common genetic driver of LCH. We show that BRAFV600E/WT iPSCs display myelo-monocytic skewing during hematopoiesis and spontaneously differentiate into CD1a+/CD207+ cells that are similar to lesional LCH cells and are derived from a CD14+ progenitor. We show that BRAFV600E modulates the expression of key transcription factors regulating monocytic differentiation and leads to an upregulation of pro-inflammatory molecules and LCH marker genes early during myeloid differentiation. In vitro drug testing revealed that BRAFV600E-induced transcriptomic changes are reverted upon treatment with MAPK-pathway inhibitors (MAPKi). Importantly, MAPKi do not affect myeloid progenitors but reduces only the mature CD14+ cell population. Furthermore, iPSC-derived neurons (iNeurons) co-cultured with BRAFV600E/WT iPSC-derived microglia-like cells (iMGL), differentiated from iPSC-derived CD34+ progenitors, exhibit signs of neurodegeneration with neuronal damage and release of neurofilament light chain. In summary, the iPSC-based model described here provides a platform to investigate the effects of BRAFV600E in different hematopoietic cell types and provides a tool to compare and identify novel approaches for the treatment of BRAFV600E-driven diseases.

Transcriptomic analysis delineates potential regulatory network as therapeutic alternatives in chronic myeloid leukemia

BackgroundChronic myeloid leukemia (CML) relapse and progression after discontinuation of tyrosine kinase inhibitors (TKI) therapy in the chronic phase (CP) are attributed to primitive quiescent leukemic progenitor cells (LPCs). This study aimed to identify key differentially expressed genes (DEGs) involved in molecular pathways alternative to BCR-ABL, which could lead to the eradication of leukemic stem/progenitor cells.MethodsmRNA expression profiling dataset comprising newly diagnosed untreated CP CML leukemic progenitor cell samples n=5 and normal hematopoietic progenitor cell samples n=5 were selected for DEGs identification. A weighted gene co-expression network was constructed to identify significant hub modules. Protein–protein interaction (PPI) network construction and pathway enrichment analysis provided additional information on the biological pathways involved. The genes involved in the resultant PPI network were subjected to a gene transcriptional regulatory network based on transcription factors (TFs) and microRNAs (miRNAs) involved in the target genes.ResultsA total of 709 genes that were differentially expressed among those corresponding to p<0.05 and log2FC>0.5 0.5$$\\end{document}]]>. The WGCNA showed a significant hub module comprising 267 DEGs. The major pathways of the hub genes involved in the PPI network at the highest confidence score >0.9 0.9$$\\end{document}]]> were related to mitochondrial translational elongation. The integrated gene transcriptional regulatory network revealed a TF (ETS1), two miRNAs (miR-34a-5p and miR-205-5p) targeting a hub gene (GFM1) as the highest-order motif or subnetwork in the three-node miRNA feed-forward loop.ConclusionsThe study suggests that the regulatory feed-forward loop may provide a potential therapeutic target in CML. Consequently, the mitochondrial translation pathway may be explored as an alternative to BCR-ABL pathways, which could aid in eliminating or increasing sensitization of CML progenitor/stem cells to TKI treatment.

Emerging concepts of CMV in transplantation

AbstractCytomegalovirus (CMV) infections continue to be associated with significant morbidity and mortality following solid organ transplantation and haemopoietic stem cell transplantation. Advances in understanding the biology of CMV in the immunosuppressed host will translate into improved management approaches and better clinical outcomes. Updated definitions of resistant and refractory CMV infections will lead to more consistent reporting of CMV outcomes, better inform appropriate antiviral strategies and influence clinical trial design. Improved knowledge of the immunological control of CMV in the immunosuppressed host has led to novel diagnostics, emerging therapeutic cellular therapies and the development of an informed rationale for prophylactic and pre‐emptive strategies. As the boundaries of transplantation are extended, new patterns of CMV infection are being recognised. Finally, recent studies support the use of novel antiviral therapies in transplant recipients in the appropriate clinical setting. In this review, we provide an update on important new and emerging concepts in the management of CMV in immunosuppressed transplant recipients.

The impact of patient ethnicity on haematopoietic cell transplantation outcome: a retrospective cohort study on the UK experience

The impact of patient ethnicity on haematopoietic cell transplantation outcome: a retrospective cohort study on the UK experience

Hematopoietic cell transplantation in CR1 may help mitigate the adverse outcomes of Ph-like B-ALL in adult patients

Hematopoietic cell transplantation in CR1 may help mitigate the adverse outcomes of Ph-like B-ALL in adult patients

Measuring the Effect of Newborn Screening on Survival After Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency: A 36-Year Longitudinal Study From the Primary Immune Deficiency Treatment Consortium.

Measuring the Effect of Newborn Screening on Survival After Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency: A 36-Year Longitudinal Study From the Primary Immune Deficiency Treatment Consortium.

A Pax3 lineage gives rise to transient haematopoietic progenitors.

During embryonic development, muscle tissues, skin, and a subset of vascular endothelial cells arise from Pax3-expressing embryonic progenitors defined as paraxial mesoderm. By contrast, haemogenic potential is well established for extra-embryonic mesoderm and intra-embryonic lateral plate mesoderm, which do not express Pax3. To date, it is not known whether the haematopoietic system also contains Pax3 lineage cells. Here, we show that the mouse foetal liver and foetal circulation contain a transient population of Pax3 lineage cells with hallmarks of haematopoietic progenitors and the potential to generate both myeloid and erythroid cells. We propose that Pax3 lineage haematopoietic cells should be investigated to better understand normal haematopoietic development from different mesodermal derivatives. Further, genetic alterations of Pax3 lineage haematopoietic cells should be investigated for their potential to cause haematopoietic malignancies.

Prognostic Factors Associated With Increased Mortality in Pediatric Veno-Occlusive Disease Following Hematopoietic Cell Transplantation.

Hepatic veno-occlusive disease (VOD) is a life-threatening complication of hematopoietic cell transplantation (HCT) and is categorized as a transplant-related, systemic endothelial disease. Severe VOD can lead to multi-organ dysfunction (MOF) and is associated with a high mortality rate. To evaluate the incidence of VOD in children after HCT and analyze the outcomes and risk factors associated with increased mortality. A retrospective cohort study of 1243 children with malignant and non-malignant diseases who underwent HCT at two large pediatric centers over 20 years. One hundred one patients (8%) developed VOD post HCT. Most patients developed VOD post allogeneic HCT (76%) versus autologous (24%). The incidence of VOD was twice as high in children with malignant diseases compared to non-malignant (68%vs. 32%). A much higher incidence of VOD occurred in patients after a busulfan-based regimen versus total body irradiation-based and treosulfan-based, 73%, 18%, and 1%, respectively. The 100-day survival rate of HCT patients with VOD was 69%. The overall survival rate of the entire group was 50%, showing improvement over the span of the study years, from 40% between 2000 and 2009 to 63% between 2010 and 2021 (p = 0.022). Factors associated with increased mortality included infections before transplant (p = 0.013), conditioning regimen (p = 0.01), abnormal liver function (p = 0.019), presence of ascites (p = 0.008), MOF (p < 0.001), and the need for admission to a pediatric intensive care unit (p < 0.001). There was no significant difference in survival rates between children treated with defibrotide alone or with those treated with defibrotide and steroids (61% and 65%, respectively; p = 0.685). Severe VOD in pediatric patients following HCT remains a life-threatening complication with a high mortality rate. Early diagnosis and treatment with defibrotide are critical for managing this condition. In our cohort, the addition of steroids to defibrotide was not associated with improved outcomes.

Human umbilical cord mesenchymal stem cells improve bone marrow hematopoiesis through regulation of bone marrow adipose tissue.

Bone marrow adipose tissue (BMAT) exhibits a multitude of biological functionalities and influences hematopoiesis. The adiposity status of the bone marrow may play a role in the decline of hematopoietic function. Mesenchymal stem cells (MSCs) constitute crucial regulators within the bone marrow microenvironment; however, their precise role in modulating BMAT and the subsequent implications for hematopoiesis remain poorly understood. We conducted in vivo studies to observe the effects of human umbilical cord mesenchymal stem cells (hucMSCs) on BMAT accumulation and restoration of hematopoietic function in mice with drug-induced hematopoietic impairment. Concurrently, in vitro co-culture experiments were used to investigate the impact of hucMSCs on preadipocytes and mature adipocytes, and the potential subsequent consequences for hematopoietic cells. Moreover, we explored the potential mechanisms underlying these interactions. Our findings reveal that hucMSCs concomitantly mitigate BMAT accumulation and facilitate the recovery of hematopoietic function in mouse models with drug-induced hematopoietic impairment. In vitro, hucMSCs potentially impede adipogenic differentiation of 3T3-L1 preadipocytes through interference with the JAK2/STAT3 signaling pathway and affect the functionality of mature adipocytes, thus mitigating the detrimental effects of adipocytes on hematopoietic stem cells (HSCs). Furthermore, we demonstrate that hucMSCs may protect hematopoietic cells from adipocyte-induced damage by protecting antioxidative mechanisms. These results suggest that hucMSCs exhibit an inhibitory effect on the excessive expansion of adipose tissue and modulate adipose tissue function, which may potentially contribute to the regulation of the bone marrow microenvironment and favorably influence hematopoietic function improvement.

Co-existent MDS and lymphoma in a young pregnant woman: A case report and literature review

Myelodysplastic neoplasms (MDS) represent a diverse group of clonal myeloid disorders marked by ineffective hematopoiesis, leading to cytopenias and dysplastic hematopoietic cells. Rarely, MDS may coexist with Non-Hodgkin Lymphoma (NHL), often emerging as a secondary complication post-lymphoma treatment. However, concurrent diagnosis of MDS and lymphoma prior to any chemotherapy or radiotherapy exposure is uncommon. This article discusses a rare case of co-existent MDS and T-cell lymphoma in a young pregnant woman, along with a literature review. Clinical findings, laboratory results, and bone marrow aspiration indicated the presence of both MDS and NHL, with subsequent lymph node biopsy confirming T-cell lymphoma. Literature reveals multiple hypotheses for the coexistence of MDS and lymphomas, including common pathogenic pathways, overlapping genetic mutations, or shared immunological abnormalities. Mutations like TP53, ASXL1, DNMT3A, and RUNX1 are frequently implicated in both MDS and lymphoma and suggest a potential common origin for these diseases. Prognosis remains poor for patients with concurrent MDS and NHL due to limited therapeutic options. Treatment is complex and must consider patient age, comorbidities, and MDS and lymphoma subtypes. Advances in genetic analysis provide insights into the shared etiology of these diseases, potentially aiding in future therapeutic approaches. This case underscores the clinical and therapeutic challenges presented by concurrent MDS and lymphoma and highlights the need for specific management strategies.

Germline BRCA pathogenic variants and hematologic adverse events in patients with ovarian carcinoma receiving PARP inhibitors: a retrospective cohort study.

Patients with a germline BRCA pathogenic variant (gBRCA-PV) and advanced high grade ovarian carcinoma (aHGOC) experience higher hematologic adverse events (HAEs) when receiving platinum salts and ionizing radiations, compared to non-carriers, due to a possible higher susceptibility of the hemopoietic stem cells to DNA targeting agents. However, the incidence of PARP inhibitor (PARPi)-related HAEs according to the gBRCA-PV status is currently unknown. We conducted a single-center retrospective cohort study to describe the occurrence of HAEs in patients with aHGOC receiving ≥8 weeks of maintenance PARPi in any line of therapy, comparing gBRCA-PVs carriers to non-carriers. HAEs were manually identified by searching the patients' electronic medical records and classified by CTCAE v5.0. The main endpoint was the incidence rate of any HAE (ie, anaemia, neutropenia, or thrombocytopenia) of grade 2 or more (G ≥ 2). One hundred and sixty-six patients were included; 95 (57%) had a gBRCA-PV. In total, 162 incident cases of G ≥ 2 HAEs were reported over 255.3 person-years. The incidence rates of G ≥ 2 HAEs were 1003/1000 person-years in gBRCA-PV carriers and 993/1000 person-years in non-carriers. No difference in the incidence rate of G ≥ 2 HAEs emerged comparing gBRCA-PV carriers to non-carriers (crude-incidence rate ratio [IRR]: 1.01; 95% CI: 0.72, 1.43; P = .96), even after adjusting for the type of PARPi (Mantel-Haenszel IRR: 0.99; 95% CI: 0.67, 1.46). Patients with aHGOC and a gBRCA-PV do not experience higher PARPi-related HAEs compared to non-gBRCA-PV carriers, unlike platinum salt-related HAEs.

Work Participation of Hematological Cancer Survivors AfterHematopoietic Cell Transplantation: A Scoping Review.

Hematopoietic cell transplantation (HCT) is a common treatment for people diagnosed with hematological cancers. However, it can cause side effects that may affect work participation. This scoping review aims to provide an overview of the factors that influence the work participation of hematological cancer survivors who have undergone HCT. We conducted a scoping review following the Joanna Briggs Institute guidelines and developed our search strategy in collaboration with a scientific librarian and searched nine databases (CINAHL, MEDLINE, EMBASE, Cochrane, PubMed, PsycINFO, Web of Science, Scopus, ProQuest Dissertations, & Theses Global) for primary studies in French or English until February 2024. Two reviewers extracted the data and analyzed it thematically. We synthesized and presented the findings using a narrative description approach. We identified 940 publications, of which 36 met the eligibility criteria. Our findings underscore the significance of considering individuals over 50, those undergoing allogeneic HCT, women, and those with lower incomes. We noted disparities in evaluating or describing work participation. It is crucial for researchers and healthcare professionals in hematological care to be aware of the intersecting factors that influence work participation. There are still significant gaps in how workplace dynamics, legislation, and healthcare systems affect the return to work process.

Targeting chromatin modifying complexes in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a devastating hematologic malignancy with high rates of relapse, which can, in part, be attributed to the dysregulation of chromatin modifications. These epigenetic modifications can affect the capacity of hematopoietic cells to self-renew or differentiate, which can lead to transformation. Aberrant histone modifications contribute to the derepression of self-renewal genes such as HOXA/B and MEIS1 in committed hematopoietic progenitors, which is considered a key mechanism of leukemogenesis in MLL-rearranged (MLL-r) and NPM1-mutated AML. As regulators of some of the key histone modifications in this disease, the menin-KMT2A and polycomb repressive (PRC1/2) complexes have been identified as promising targets for the treatment of AML. This review explores recent discoveries of how leukemic cells hijack these complexes and their interactions with other chromatin regulators to promote disease progression. We also discuss inhibitors targeting these complexes that have demonstrated therapeutic efficacy in preclinical and clinical studies and propose novel therapeutic combinations targeting the KMT2A and PRC1/2 broader interacting networks to overcome issues of resistance to existing monotherapies.

Methotrexate Versus Mycophenolate Mofetil Prophylaxis inAllogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Malignancies: A Retrospective Analysis on Behalf of the Chronic Malignancies Working Party of the EBMT.

Prophylaxis strategies for Graft versus host disease (GVHD) in allogeneic hematopoietic cell transplantation (allo-HCT) frequently encompass a combination of a calcineurin inhibitor (CNI) with either methotrexate (MTX) or mycophenolate mofetil (MMF). The aim of this retrospective, EBMT registry-based study was to determine outcome differences for chronic myeloid malignancies and secondary acute myeloid leukemia (sAML) between MTX- and MMF-based prophylaxis regimens while taking potential heterogeneity between subgroups into consideration. Eligible were patients transplanted between 2007 and 2017 who received either MTX- or MMF prophylaxis in combination with a CNI. Endpoints after allo-HCT were overall survival, relapse-free survival (RFS), relapse incidence, non-relapse mortality (NRM), and Grades 2-4 acute GVHD (aGvHD). Overall, 13 699 patients from 321 centers were included. Median follow-up was 42.8 months (IQR 19.8-74.5 months). MTX prophylaxis was associated with reduced overall mortality (HR 0.87, 95% CI 0.81-0.95, p = 0.001) and NRM (HR 0.86, 95% CI 0.78-0.96, p = 0.006) compared with MMF in multivariable Cox regression models in the whole cohort without significant interaction between prophylaxis and subgroups. In contrast, there was no significant association of prophylaxis with risk of relapse (HR 1.03 MTX vs. MMF, 95% CI 0.94-1.14, p = 0.53) or RFS (HR 0.95, 95% CI 0.88-1.01, p = 0.12). There was a reduced risk of Grades 2-4 acute GVHD and reduced mortality after acute GVHD with MTX prophylaxis but no association with outcome in a landmark analysis in patients without aGvHD at 3 months after allo-HCT. In conclusion, MTX-complemented CNI prophylaxis was associated with favorable survival, and with favorable survival after aGVHD compared with MMF.

A sex-dependent salivary bacterium influences oral mucositis severity after allogeneic hematopoietic cell transplantation

The success of allogeneic hematopoietic cell transplantation (alloHCT) in curing hematologic disorders is limited by its short- and long-term toxicities. One such toxicity is oral mucositis (OM), causing pain, speech/swallowing difficulty, and prolonged hospitalization. Although conditioning chemoradiotherapy is the direct cause of OM, potential host-intrinsic mediators of mucosal injury remain elusive. We hypothesized that the oral microbiota may influence OM severity. We used a validated comprehensive scoring system based on specialized Oral Medicine examinations to longitudinally quantify OM severity in alloHCT recipients. High-throughput multi-site profiling of the oral microbiota was performed in parallel. We identify a sex-dependent commensal bacterium, Oribacterium asaccharolyticum, whose presence in saliva before transplantation is associated with more severe OM 14 days after transplantation. The sex predilection of this species correlated with higher uric acid levels in men. Our findings represent the first sex-dependent microbiota-mediated pathway in OM pathogenesis and introduce novel targets for preventative interventions.

Is Allogeneic Transplantation for Sickle Cell Disease Still Relevant in the Era of Gene Therapy?

Sickle cell disease (SCD) is the most common inherited blood disease. Disease-modifying therapy and supportive care have improved the survival of children with SCD in the United States and Europe. Yet, adults with SCD continue to have high risks of morbidity and early death. Recently, two FDA-approved genetic therapies offer the potential for a short-term decrease in acute vaso-occlusive pain events if not cure. Allogeneic hematopoietic cell transplantation (alloHCT) is also curative, but until recently was constrained by limited donor availability and the risks of graft-versus-host disease, graft rejection, and death. Importantly, recent advances have attenuated these barriers. Here, we discuss the current state of therapies with curative intent for SCD. Both genetic therapy and alloHCT offer the potential for cure for most with SCD. However, the cost (about five times higher), the current need for myeloablation, and associated late-health effects may make genetic therapies less favorable choices than alloHCT.

HCT in the widening spectrum of congenital immunodeficiencies.

Hematopoietic stem cell transplantation (HSCT) and inborn errors of immunity (IEI) have been closely linked since transplantation was first used to cure severe combined immunodeficiency (SCID) in 1968. Since then, novel genes and diseases have been continually added to the ongoing list of IEI, and new data on indications and outcomes have emerged. We review recent data and progress in the field of hematopoietic cell transplantation (HCT) for IEI including new diseases and complications. Emerging data from haploidentical transplants, newborn screening results, and multicentric studies reveals promising outcomes for IEI. Immune dysregulation diseases deserve special attention regarding disease control and may require additional drugs pretransplant. Female carriers of X-linked Chronic granulomatous may present with a severe phenotype warranting the need for HCT. Insights from infectious complications and long-term comorbidities should help guide decisions to treat IEI patients. From classical indications to recently described diseases, HCT for immunodeficiencies is a rapidly growing field. Novel data regarding alternative donor transplants, results from large cohorts, and long-term complications provide valuable knowledge for clinical practice.