Role of allogeneic hematopoietic cell transplantation in VEXAS syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a newly diagnosed syndrome comprising severe systemic inflammatory and hematological manifestations including myelodysplastic syndrome and plasma cell dyscrasia. Since its discovery four years ago, several groups have identified pleomorphic clinical phenotypes, but few effective medical therapies exist which include Janus Kinase (JAK) inhibitors, interleukin inhibitors (IL-1 and IL-6), and hypomethylating agents. Prospective trials are lacking at this time and most patients remain corticosteroid dependent. VEXAS has a high morbidity from frequent life threatening inflammatory symptoms and risk of progression to hematological malignancies and has an overall survival of 50% at 10 years. Allogeneic stem cell transplant (allo-HCT) is a curative option for this disease caused by somatic mutations in the UBA1 gene. Here we outline the role of allo-HCT in treating patients with VEXAS syndrome, highlighting the outcomes from several single-institution studies and case reports. Prospective trials will be required to precisely define the role of allo-HCT in the management of VEXAS syndrome.

Ischemic stroke as the initial presentation in acute myeloid leukemia vs. myelodysplastic syndrome: a case report and literature review with pathophysiological and clinical exploration.

BACKGROUND: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) present intricate challenges due to their diverse clinical manifestations and thrombotic complications. Thromboembolism (TE) incidence in newly diagnosed AML patients is noteworthy, with arterial TE linked to poorer overall survival. Ischemic strokes, although relatively low in prevalence, carry significant clinical implications. CASE DESCRIPTION: We report the case of an 84-year-old male with Type 2 Diabetes, Hypertension, and Chronic Kidney Disease, presenting with seizures, focal neurological deficits, and pancytopenia. An unexpected diagnosis of AML or MDS emerged during the investigation. Despite interventions, the patient's condition deteriorated, leading to a fatal outcome weeks later. CONCLUSION: This case underscores the intricate relationship between hematologic malignancies and ischemic stroke. The rarity of this complication emphasizes the importance of understanding the multifaceted mechanisms at play, including hyperleukocytosis, pro-inflammatory cytokine release, coagulation cascade activation, and direct interactions with endothelial cells. In our literature review, analysis of 15 cases, including ours, revealed a wide age range (3-87 years) and a gender bias towards females. AML diagnosis was predominant, with uniformly low platelet counts. Cortical infarctions, especially in the anterior circulation, were common. Hyperleukocytosis, disseminated intravascular coagulation (DIC), and fatal outcomes were observed in a subset of cases. Despite the grim statistics and often poor prognosis, the identification of specific risk factors, such as thrombocytopenia and cytogenetic abnormalities, offers avenues for targeted prevention and management.

Inflamma-miRs Profile in Myelodysplastic Syndrome Patients.

Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples were collected from 20 controls and 24 MDS patients, and selected miRNs related to redox balance and inflammation (inflamma-miRs), including miR-18a, miR-21, miR-34a and miR-146a, were isolated and measured by quantitative real-time polymerase chain reaction (qRTPCR). A differential expression profile of miRNs was detected in untreated MDS patients and the 5-AZA group. Inflammation increases miRNs and, specifically, miR-18a, miR-21 and miR-34a were significantly overexpressed in untreated MDS, compared to controls. However, we did not observe any miRN profile alteration during the progression of the disease. On the other hand, 5-AZA treatment tends to restore miRN expression levels. Relating to prognostic risk factors, high-risk MDS groups (high Revised International Prognostic Scoring System (IPSS-R), high cytogenetic risk, high molecular risk (HMR) mutations) tended to be related with higher expression levels of miR-18a and miR-34a. Higher miRN expression is correlated with lower glutathione peroxidase activity, while they are related with a higher profile of pro-inflammatory cytokines (IL-2, IL-6, IL-8, TNF-α). Although our study was limited by the low number of MDS patients included, we identified miRN deregulation involved in MDS development that could regulate redox sensors and inflammatory responses. Finally, 5-AZA treatment is related with lower miRN expression levels in MDS patients.

TP53-altered acute myeloid leukemia and myelodysplastic syndrome with excess blasts should be approached as a single entity.

TP53-altered myelodysplastic syndrome with excess blasts and TP53-altered acute myeloid leukemia should be considered under one unifying classification term for their study in clinical trials. Ultimately, such a unification would simplify the screening processes for clinical trials and allow a focus on treating the patient for a genetically defined disorder rather than one based on an arbitrary blast threshold.

ETNK1 mutation occurs in a wide spectrum of myeloid neoplasms and is not specific for atypical chronic myeloid leukemia.

BACKGROUND: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms. METHODS: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1-mutated myeloid neoplasms. RESULTS: Thirty-seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the dominant clone in 63% of patients and was persistently dominant in 93%. The variant allele frequencies were usually higher in acute myeloid leukemia and increased upon leukemic transformation. ETNK1 mutation was accompanied by coexisting mutations in all patients, with ASXL1 (50%), TET2 (25%), EZH2 (24%), RUNX1 (24%), and SRSF2 (24%) mutations being the most common. Neoplasms with ETNK1 mutations were associated with morphologic dysplasia, increased blasts, myelofibrosis, and noncomplex karyotypes. With a median follow-up of 16.5 months, 30 patients died, 44 had persistent disease, and four achieved complete remission after stem cell transplantation. CONCLUSIONS: ETNK1 mutation is present in various myeloid neoplasms, often as an early event and a dominant clone and always with concurrent mutations. It may play an important role in the pathogenesis and progression of myeloid neoplasms by causing DNA damage and inducing other mutations and genomic instability, and it may serve as a potential therapeutic target. ETNK1 mutation is not disease-specific and should be interpreted with caution to classify myeloid neoplasms.

The impact of erythroblast enucleation efficiency on the severity of anemia in patients with myelodysplastic syndrome.

Anemia is the most common manifestation in myelodysplastic syndrome (MDS) patients, but the cause of ineffective hematopoiesis is not fully understood. Enucleation is an important event in the maturation process of erythroblasts. According to a series of morphological phenotypes of the pathological development of MDS erythroblasts, we speculate that there may be enucleation disorders. To verify this hypothesis, we cultured MDS bone marrow CD34+ cells in vitro and induced erythroblast development. The results showed that erythroblast enucleation in MDS was significantly lower than that in the normal group, and the rate of enucleation was positively correlated with hemoglobin concentration. Risk stratification of MDS was performed to further analyze the differences in enucleation among the normal group, low-middle risk group and high-risk group. The results showed that the enucleation rate of the high risk group was higher than that of the low-middle risk group but still lower than that of the normal group. Moreover, the expression of pERK and pAKT in MDS erythroblasts in the high risk group was higher than that in the normal group, while the expression of pERK and pAKT in the low-middle risk group was lower than that in the normal group. Furthermore, the enucleation of MDS was positively correlated with the phosphorylation degree of ERK and AKT. In conclusion, this study reveals that the enucleation of erythroblasts is one of the possible causes of anemia in MDS. Video Abstract.

Is Treosulfan-Based Conditioning Attractive as a Reduced-Intensity Conditioning Regimen in Korea?

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) was not actively performed in elderly acute myeloid leukemia (AML) or myelodysplastic syndrome patients who are at a high-risk based on hematopoietic cell transplantation-specific comorbidity index (HCT-CI). The advent of reduced-intensity conditioning (RIC) regimens has made HSCT applicable in this population. However, the selection of appropriate conditioning is a major concern for the attending physician. The benefits of combination of treosulfan and fludarabine (Treo/Flu) have been confirmed through many clinical studies. Korean data on treosulfan-based conditioning regimen are scarce. METHODS: A retrospective study was conducted to compare the clinical outcomes of allogeneic HSCT using RIC between 13 patients receiving Treo/Flu and 39 receiving busulfan/fludarabine (Bu/Flu). RESULTS: In terms of conditioning-related complications, the frequency of ≥ grade 2 nausea or vomiting was significantly lower and the duration of symptoms was shorter in the Treo/Flu group than in the Bu/Flu group. The incidence of ≥ grade 2 mucositis tended to be lower in the Treo/Flu group. In the analysis of transplant outcomes, all events of acute graft versus host disease (GVHD) and ≥ grade 2 acute GVHD occurred more frequently in the Treo/Flu group. The frequency of Epstein-Barr virus reactivation was significantly higher in the Treo/Flu group (53.8% vs. 23.1%, P = 0.037). Non-relapse mortality (NRM) at 12 months was higher in the Treo/Flu group (30.8% vs. 7.7%, P = 0.035). Significant prognostic factors included disease type, especially secondary AML, disease status and high-risk based on HCT-CI, ≥ grade 2 acute GVHD, and cases requiring ≥ 2 immunosuppressive drugs for treating acute GVHD. In the comparison of survival outcomes according to conditioning regimen, the Bu/Flu group seemed to show better results than the Treo/Flu group (60% vs. 46.2%, P = 0.092 for overall survival; 56.4% vs. 38.5%, P = 0.193 for relapse-free survival). In additional analysis for only HCT-CI high-risk groups, there was no difference in transplant outcomes except that the Treo/Flu group tended to have a higher NRM within one year after transplantation. Survival outcomes of both groups were similar. CONCLUSION: This study suggests that Treo/Flu conditioning may be an alternative to Bu/Flu regimen in elderly patients with high-risk who are not suitable for standard conditioning.

[Clinical significance of clonal hematopoiesis and disease boundaries in bone marrow failure diseases].

Aplastic anemia (AA) is a non-neoplastic bone marrow failure syndrome caused by the destruction of hematopoietic stem and progenitor cells by the immune system. However, in some cases of AA, a small number of specific clones with gene mutations are observed without clinical manifestations. Cases with mutated PIG-A, BCOR/BCORL1, or HLA class I allele clones respond better to immunosuppressive therapies (ISTs). Cases with MDS-related clones, such as DNMT3A or ASXL1 mutations, are at a higher risk for secondary MDS. In this review, I will focus on the clonal hematopoiesis (CH) in AA and discuss its clinical significance, including its impact on disease boundaries and transition. I will also discuss the pathophysiology and diagnosis of hypoplastic MDS, a type of MDS that responds to ISTs.

Germline ERCC excision repair 6 like 2 (ERCC6L2) mutations lead to impaired erythropoiesis and reshaping of the bone marrow microenvironment.

Despite the inclusion of inherited myeloid malignancies as a separate entity in the World Health Organization Classification, many established predisposing loci continue to lack functional characterization. While germline mutations in the DNA repair factor ERCC excision repair 6 like 2 (ERCC6L2) give rise to bone marrow failure and acute myeloid leukaemia, their consequences on normal haematopoiesis remain unclear. To functionally characterise the dual impact of germline ERCC6L2 loss on human primary haematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs), we challenged ERCC6L2-silenced and patient-derived cells ex vivo. Here, we show for the first time that ERCC6L2-deficiency in HSPCs significantly impedes their clonogenic potential and leads to delayed erythroid differentiation. This observation was confirmed by CIBERSORTx RNA-sequencing deconvolution performed on ERCC6L2-silenced erythroid-committed cells, which demonstrated higher proportions of polychromatic erythroblasts and reduced orthochromatic erythroblasts versus controls. In parallel, we demonstrate that the consequences of ERCC6L2-deficiency are not limited to HSPCs, as we observe a striking phenotype in patient-derived and ERCC6L2-silenced MSCs, which exhibit enhanced osteogenesis and suppressed adipogenesis. Altogether, our study introduces a valuable surrogate model to study the impact of inherited myeloid mutations and highlights the importance of accounting for the influence of germline mutations in HSPCs and their microenvironment.

Somatic mutations show no clear association with red blood cell or human leukocyte antigen alloimmunization in de novo or therapy-related myelodysplastic syndrome.

BACKGROUND: Myelodysplastic syndrome (MDS) is a marrow failure disease. As patients often require chronic transfusion, many develop red blood cell (RBC) alloimmunization or immune-mediated platelet refractoriness. MDS represents a spectrum of diseases with specific categorizations and genetic abnormalities, and we set out to determine if these characteristics predispose patients to antibody formation. STUDY DESIGN AND METHODS: A natural language search identified MDS patients with pre-transfusion testing from 2015 to 2020. Marrow reports, cytogenetic results, and next-generation sequencing panels were gathered. Transfusion history and testing were collected from the laboratory information system. RESULTS: The group consisted of 226 biopsy-proven MDS patients. The prevalence of RBC alloimmunization was 11.1% (25 of 226). Half (23 of 46) of all RBC alloantibodies were against Rh (C, c, E, e) and Kell (K) antigens. There was a relative enrichment for JAK2 positivity among the RBC alloimmunized group. A total of 7.1% (16 of 226) of patients had immune-mediated platelet refractoriness and had increased transfusion requirements (p ≤ 0.01). No disease type or genetic abnormality was significantly associated with alloimmunization or immune-mediated platelet refractoriness. DISCUSSION: While JAK2 specific mutations were enriched among RBC alloimmunized patients, this association failed to reach statistical significance in our single-center cohort. Further study using larger patient cohorts is warranted. Overall, this cohort of MDS patients had very similar RBC alloimmunization prevalence and anti-RBC antibody specificities as other recent literature. Our data reinforce the finding that MDS patients are at greater risk for alloimmunization and support the use of extended phenotype matching for these at-risk patients.

Pathological features of inflammatory myopathy as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation.

Chronic graft-versus-host disease (cGVHD) is the most important complication resulting in the death of bone marrow transplantation (BMT) survivors. It is also a relatively rare cause of inflammatory myopathy (IM). We report the case of a 46-year-old woman who developed severe cGVHD-related IM after BMT for myelodysplastic syndrome. She presented with severe muscle pain and weakness with cGVHD-related symptoms in other organs. Myopathological analysis showed moderate cell infiltration with remarkable necrotic and regenerative fibers. Sarcoplasm and capillaries expressed C5b9 and myxovirus resistance protein 1. Non-necrotic fibers in perifascicular regions expressed MHC-II. Steroid therapy did not sufficiently control cGVHD-related IM, and the patient was concurrently treated with an immunosuppressant. Our findings show that IM is a key manifestation of cGVHD and that the expression of interferon-inducible proteins in muscle pathology is useful for identifying cGVHD-related IM.

TET2 Mutation and High miR-22 Expression as Biomarkers to Predict Clinical Outcome in Myelodysplastic Syndrome Patients Treated with Hypomethylating Therapy.

Tet methylcytosine dioxygenase 2 (TET2) is one of the most frequently mutated genes in myelodysplastic syndrome (MDS). TET2 is known to involve a demethylation process, and the loss of TET2 is thought to cause DNA hypermethylation. Loss of TET2 function is known to be caused by genetic mutations and miRNA, such as miR-22. We analyzed 41 MDS patients receiving hypomethylating therapy (HMT) to assess whether TET2 mutation status and miR-22 expression status were associated with their clinical characteristics and treatment outcomes. Responsiveness to HMT was not affected by both TET2 mutation (odds ratio (OR) 0.900, p = 0.909) and high miR-22 expression (OR 1.548, p = 0.631). There was a tendency for TET2 mutation to be associated with lower-risk disease based on IPSS (Gamma = -0.674, p = 0.073), lower leukemic transformation (OR 0.170, p = 0.040) and longer survival (Hazard ratio 0.354, p = 0.059). Although high miR-22 expression also showed a similar tendency, this tendency was weaker than that of TET2 mutation. In summary, the loss of TET2 function, including both TET2 mutation and high miR-22 expression, was not a good biomarker for predicting the response to HMT but may be associated with lower-risk disease based on IPSS, lower leukemic transformation and longer survival.

Fractionated busulfan myeloablative conditioning improves survival in older patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown. METHODS: Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 µmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 µmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m2 intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival. RESULTS: Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01). CONCLUSIONS: A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.

Clinical value of next-generation sequencing compared to cytogenetics in patients with suspected myelodysplastic syndrome.

Next-generation sequencing (NGS) increasingly influences diagnosis, prognosis and management of myelodysplastic syndrome (MDS). In addition to marrow morphology and flow cytometry, our institution performs cytogenetics (CG) and NGS-based testing routinely in patients with suspected MDS. We evaluated the relative value of NGS in the assessment of patients with suspected MDS. We initially compared the diagnostic and prognostic information derived from CG and NGS in 134 patients. NGS enhanced the diagnostic yield compared to CG for clonal myeloid disorders (sensitivity 77% vs. 42·2%; specificity 90·2% vs. 78%; positive predictive value 92·8% vs. 76%; and negative predictive value 70·8% vs. 45·5%). The identification of poor prognosis mutations by NGS altered risk category in 27/39 (69·2%) patients with MDS with good/intermediate risk CG. Subsequently, we prospectively evaluated 70 patients with suspected MDS using an 'NGS-first approach' with CG restricted to samples with morphological abnormalities. We rarely identified mutations or CG abnormalities in patients without dysplastic features. NGS has a superior diagnostic performance compared to CG in patients with suspected MDS. We estimate that by using an 'NGS-first approach' we could reduce karyotyping by approximately 30%.

Therapy-related myeloid neoplasm after peptide receptor radionuclide therapy (PRRT) in 1631 patients from our 20 years of experiences: prognostic parameters and overall survival.

PURPOSE: To determine prognostic factors and overall survival (OS) in therapy-related myeloid neoplasm (t-MN) of patients after receiving peptide receptor radionuclide therapy (PRRT). METHODS: All patients treated from February 1999 until September 2019 at our center who had bone marrow biopsy-proven t-MN after PRRT were included. Patient characteristics, laboratory results, and all tumor-directed therapies before t-MN diagnosis were collected. Cox regression analysis was performed to identify parameters associated with OS. Receiver operating characteristic (ROC) curve analysis was used to define cutoff values as well as sensitivity and specificity of the parameters. RESULTS: Out of 1631 patients treated with PRRT, 30 patients developed t-MN comprising myelodysplastic syndrome (MDS) in 23 patients (77%) and acute myeloid leukemia (AML) in 7 patients (23%). The median OS of t-MN patients was 13 months (range 9.1-16.9 months): 6 months for AML and 15 months for the MDS subgroup, respectively. Higher platelet level was a significant prognostic parameter for longer OS (hazard ratio (HR): 0.99, P < 0.05). Using ROC analysis, the best cutoff value for thrombocyte count was 183.5 Gpt/L, resulting in a sensitivity of 92.3% and a specificity of 50%. Other factors, such as hemoglobin level, did not show a significant correlation with OS. CONCLUSION: Even rarely occurred, the OS is gravely compromised in t-MN patients after PRRT, and even less in the AML subgroup (6 months). Higher platelet value was a significant prognostic parameter for longer OS in t-MN patients.

Upregulated hypoxia inducible factor 1α signaling pathway in high risk myelodysplastic syndrome and acute myeloid leukemia patients is associated with better response to 5-azacytidine-data from the Hellenic myelodysplastic syndrome study group.

5-azacytidine (5-AZA) is considered the standard of care for patients with high-risk myelodysplastic syndromes (MDS) and patients with acute myeloid leukemia (AML) not candidate for intensive chemotherapy. However, even after an initial favorable response, almost all patients relapse, with the exact mechanisms underlying primary or secondary 5-AZA resistance remaining largely unknown. Several reports have previously demonstrated the significance of hypoxia in the regulation of both physiological and malignant hematopoiesis. In MDS, high hypoxia inducible factor 1α (Hif-1α) expression has been correlated with poor overall survival and disease progression, while its involvement in the disease's pathogenesis was recently reported. We herein investigated the possible association of the Hif-1α signaling pathway with response to 5-AZA therapy in MDS/AML patients. Our data demonstrated that 5-AZA-responders present with higher Hif-1α mRNA and protein expression compared to 5-AZA-non-responders/stable disease patients, before the initiation of therapy, while, interestingly, no significant differences in Hif-1α mRNA expression at the 6-month follow-up were observed. Moreover, we found that 5-AZA-responders exhibited elevated mRNA levels of the Hif-1α downstream targets lactate dehydrogenase a (LDHa) and BCL2 interacting protein 3 like (BNIP3L), a further indication of an overactivated Hif-1a signaling pathway in these patients. Kaplan-Meier survival analysis revealed a significant correlation between high Hif-1α mRNA expression and better survival rates, while logistic regression analysis showed that Hif-1α mRNA expression is an independent predictor of response to 5-AZA therapy. From the clinical point of view, apart from proposing Hif-1α mRNA expression as a significant predictive factor for response to 5-AZA, our data offer new perspectives on MDS combinational therapies, suggesting a potential synergistic activity of 5-AZA and Hif-1α inducers, such as propyl hydroxylases inhibitors (PHDi).

Current Management and New Developments in the Treatment of Myelodysplastic Syndrome.

Myelodysplastic syndrome (MDS) is a heterogeneous hematological neoplasm with a wide range of clinical presentations from isolated anemia to pancytopenia and propensity to transform to acute myeloid leukemia. MDS is characterized by morphologic bone marrow dysplasia and ineffective hematopoiesis resulting from a range of cytogenetic abnormalities and somatic gene mutations. Disease management varies from observation alone for low-risk disease to hypomethylating agents and hematopoietic cell transplantation (HCT) for higher risk disease. In this chapter, we review the classification, risk stratification, and optimal management of patients with MDS.

Patient Selection and Toxicities of PRRT for Metastatic Neuroendocrine Tumors and Research Opportunities.

OPINION STATEMENT: Neuroendocrine tumors (NETs) are a heterogenous group of neoplasms characterized by varied biological hallmarks and behavior, ranging from indolent to aggressive. For many decades, somatostatin analogues and few targeted therapies were available for NETs and these therapies had minimal response rates. However, there have been a number of recent treatment advances. Peptide receptor radionuclide therapy (PRRT) is a novel approach to treatment of NETs and has changed the landscape of treatment for NETs. It is a form of targeted therapy in which a radiolabeled somatostatin analogue delivers radiation specifically to tumor cells expressing the somatostatin receptor.

The Effects of Human BDH2 on the Cell Cycle, Differentiation, and Apoptosis and Associations with Leukemia Transformation in Myelodysplastic Syndrome.

Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2mRNA expression in BM is observed in MDS patients (n = 187 vs. 43, normal BM; P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; P = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.

Tumor genetic alterations and features of the immune microenvironment drive myelodysplastic syndrome escape and progression.

The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34+ blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.