Telomeres are specific nucleoprotein structures at the ends of eukaryotic chromosomes. Telomeres and telomere-associated proteins maintain genome stability by protecting the ends of chromosomes from fusion and degradation. In normal somatic cells, the length of the telomeres gradually becomes shortened with cell division. In tumor cells, the shortening of telomeres length is accelerated under the increased proliferation pressure. However, it will be maintained at an extremely short length as the result of activation of telomerase. Significantly shortened telomeres, activation of telomerase, and altered expression of telomere-associated proteins are common features of various hematologic malignancies and are related with progression or chemotherapy resistance in these diseases. In patients who have received hematopoietic stem cell transplantation (HSCT), the telomere length and the telomerase activity of the engrafted donor cells have a significant influence on HSCT outcomes. Transplantation-related factors should be taken into consideration because of their impacts on telomere homeostasis. As activation of telomerase is widespread in tumor cells, it has been employed as a target point in the treatment of neoplastic hematologic disorders. In this review, the characteristics and roles of telomeres and telomerase both in hematologic malignancies and in HSCT will be summarized. The current status of telomerase-targeted therapies utilized in the treatment of hematologic malignancies will also be reviewed.
Although steady improvements to chemotherapeutic treatments has helped cure 80% of childhood acute lymphoblastic leukemia (ALL) cases, chemotherapy has proven to be less effective in treating the majority of adult patients, leaving allogeneic hematopoietic stem cell transplantation (allo-HSCT) as the primary adult treatment option. Nevertheless relapse are the leading cause of death following allo-HSCT. The genetic pathogenesis of relapse following allo-HSCT in Philadelphia chromosome- negative ALL (Ph− ALL) remains unexplored. We performed longitudinal whole-exome sequencing analysis in three adult patients with Ph− B-cell ALL (Ph− B-ALL) on samples collected from diagnosis to relapse after allo-HSCT. Based on these data, we performed target gene sequencing on 23 selected genes in 58 adult patients undergoing allo-HSCT with Ph− B-ALL. Our results revealed a significant enrichment of mutations in epigenetic regulators from relapsed samples, with recurrent somatic mutations in SETD2, CREBBP, KDM6A and NR3C1. The relapsed samples were also enriched in signaling factor mutations, including KRAS, PTPN21, MYC and USP54. Furthermore, we are the first to reveal the clonal evolution patterns during leukemia relapse after allo-HSCT. Cells present in relapsed specimens were genetically related to the diagnosed tumor, these cells therefore arose from either an existing subclone that was not eradicated by allo-HSCT therapy, or from the same progenitor that acquired new mutations. In some cases, however, it is possible that leukemia recurrence following allo-HSCT could result from a secondary malignancy with a distinct set of mutations. We identified novel genetic causes of leukemia relapse after allo-HSCT using the largest generated data set to date from adult patients with Ph− B-ALL.
Background. Leukemia is a common malignancy that has four main subtypes and is a threat to human health. Understanding the epidemiological status of leukemia and its four main subtypes globally is important for allocating appropriate resources, guiding clinical practice, and furthering scientific research. Methods. Average annual percentage changes (AAPCs) were calculated to estimate the change trends of age-standardized rates (ASRs) from 1990 to 2019 in 204 countries and territories. The risk factors for leukemia death and disability-adjusted life-year (DALY) were also analyzed. In addition, the future trends in ASRs were projected through 2030. Results. The total number of incident cases, deaths, and DALYs from leukemia in 2019 was 0.64, 0.33, and 11.66 million, respectively. Decreasing trends in age-standardized incidence rate (ASIR), the age-standardized death rate (ASDR), and age-standardized DALY rate were detected on a global level while increasing trends in ASIR were detected in the high-sociodemographic index (SDI) regions. The leukemia burden was heavier in males than in females. By cause, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL) were more likely to impose a burden on the elderly, while acute lymphoblastic leukemia (ALL) showed a greater impact in the younger population. A significant positive correlation was observed between SDI and AAPC in ASIR, while SDI was negatively correlated with AAPCs in both ASDR and age-standardized DALY rate. Smoking remained the most significant risk factor associated with leukemia-related death and DALY, especially in males. Similar deaths and DALYs were caused by smoking and high body mass index (BMI) in females. Future projections through 2030 estimated that ASIR and ASDR will continue to increase, while the DALY rate is predicted to decline. Conclusions. Patterns and trends of leukemia burden are correlated with SDI. The estimated contributions to leukemia deaths indicate that timely measures are needed to reduce smoking and obesity.
BackgroundDNA methyltransferase 3A (DNMT3A) mutations were considered to be independently associated with unfavorable prognosis in adults with de novo acute myeloid leukemia (AML), however, there are still debates on this topic. Here, we aim to further investigate the association between DNMT3A mutations and prognosis of patients with AML.MethodsEligible studies were identified from several data bases including PubMed, Embase, Web of Science, ClinicalTrials and the Cochrane Library (up to June 2013). The primary endpoint was overall survival (OS), while relapse-free survival (RFS) and event-free survival (EFS) were chosen as secondary endpoints. If possible, we would pool estimate effects (hazard ratio [HR] with 95% confidence interval[CI]) of outcomes in random and fixed effects models respectively.ResultsThat twelve cohort studies with 6377 patients exploring the potential significance of DNMT3A mutations on prognosis were included. Patients with DNMT3A mutations had slightly shorter OS (HR = 1.60; 95% CI, 1.31–1.95; P<0.001), as compared to wild-type carriers. Among the patients younger than 60 years of age, DNMT3A mutations predicted a worse OS (HR = 1.84; 95% CI, 1.36–2.50; P<0.001). In addition, mutant DNMT3A predicted inferior OS (HR = 2.30; 95% CI, 1.78–2.97; P = 0.862) in patients with unfavorable genotype abnormalities. Similar results were also found in some other subgroups. However, no significant prognostic value was found on OS (HR = 1.40; 95% CI, 0.98–1.99; P = 0.798) in the favorable genotype subgroup. Similar results were found on RFS and EFS under different conditions.ConclusionsDNMT3A mutations have slightly but significantly poor prognostic impact on OS, RFS and EFS of adults with de novo AML in total population and some specific subgroups.
Background Relapse represents the leading cause of death in both child and adult patients with acute lymphoblastic leukemia (ALL). Development of chemo-resistance is ultimately responsible for treatment failure and relapse, therefore understanding the molecular basis underlying resistance is imperative for developing innovative treatment strategies. Glucocorticoids (GCs) such dexamethasone and prednisolone are the backbone of combination chemotherapy regimens for treating all lymphoid tumors. However, the biological mechanisms of primary GC resistance in ALL is not completely understood. We previously performed a longitudinal whole-exome sequencing analysis on diagnosis/relapse pairs from adult patients with ALL. Our data revealed that relapse-specific truncation mutations in the NR3C1 gene, encoding the GC receptor, are frequently detected. Methods In the current study, we used discovery-based strategies including RNA sequencing (RNA-seq) and CRISPR/Cas9, followed by confirmatory testing, in human ALL cell lines, bone marrow blast samples from ALL patients and xenograft models, to elucidate the mechanisms responsible for resistance. Results Our results revealed a positive correlation between endogenous expression of NR3C1 in ALL cells and sensitivity to GCs and clinical outcomes. We further confirmed that ectopic expression of NR3C1 in ALL cells could reverse GC resistance, while deletion of NR3C1 confers resistance to GCs in ALL cell lines and xenograft models. RNA-seq analysis revealed a remarkable abundance of gene signatures involved in pathways in cancer, DNA replication, mismatch repair, P53 signalling, cell cycle, and apoptosis regulated by NR3C1. Significantly increased expression of pro-apoptotic genes including BCL2L11/Bim , BMF , BAD , BAX and BOK , and decreased transcription of anti-apoptotic genes including BCL2 , BCL2L1 and BAG2 were observed in GC-resistant ALL cells following ectopic expression of NR3C1 . Finally, we explored that GC resistance in ALL cells with haploinsufficiency of NR3C1 can be treated with Bcl-2 blockage. Conclusions Our findings suggest that the status of NR3C1 gene mutations and basal expression levels of NR3C1 in ALL cells are associated with sensitivity to GCs and clinical treatment outcomes. Early intervention strategies by rational combination of Bcl-2 blockage may constitute a promising new treatment option to GC-resistant ALL and significantly improving the chances of treating poor prednisone responders.
BackgroundThe efficient generation of hematopoietic stem cells (HSCs) from human-induced pluripotent stem cells (iPSCs) holds great promise in personalized transplantation therapies. However, the derivation of functional and transplantable HSCs from iPSCs has had very limited success thus far.MethodsWe developed a synthetic 3D hematopoietic niche system comprising nanofibers seeded with bone marrow (BM)-derived stromal cells and growth factors to induce functional hematopoietic cells from human iPSCs in vitro.ResultsApproximately 70 % of human CD34+ hematopoietic cells accompanied with CD43+ progenitor cells could be derived from this 3D induction system. Colony-forming-unit (CFU) assay showed that iPSC-derived CD34+ cells formed all types of hematopoietic colonies including CFU-GEMM. TAL-1 and MIXL1, critical transcription factors associated with hematopoietic development, were expressed during the differentiation process. Furthermore, iPSC-derived hematopoietic cells gave rise to both lymphoid and myeloid lineages in the recipient NOD/SCID mice after transplantation.ConclusionsOur study underscores the importance of a synthetic 3D niche system for the derivation of transplantable hematopoietic cells from human iPSCs in vitro thereby establishing a foundation towards utilization of human iPSC-derived HSCs for transplantation therapies in the clinic.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0326-6) contains supplementary material, which is available to authorized users.
Mobilization of mesenchymal stem cells (MSCs) is an attractive strategy for cell therapy. Our previous study demonstrated that MSCs can be mobilized in circulating blood by short-term hypoxia, and hypoxia-inducible factor-1α is essential for MSC mobilization. In the present study, the effect of the hypoxia-mimicking agent CoCl was examined on MSC mobilization. The results indicated that the frequency of circulating MSCs increased slightly by administration of CoCl. However, the mobilization efficiency was low. Considering the critical role of stromal cell-derived factor-1α (SDF-1)/CXCR4 axis in the regulation of MSC migration, the effects of granulocyte colony-stimulating factor (G-CSF) and the CXCR4 antagonist AMD3100 were investigated on MSC mobilization. The experiments were notably demonstrated in animals preconditioned with CoCl. The frequency of colony-forming unit fibroblast and the proportion of CD45CD90 cells did not significantly increase in the peripheral blood of rats treated with G-CSF and/or AMD3100 alone. The concomitant administration of G-CSF with CoCl could not stimulate the release of MSCs. However, AMD3100 dramatically increased MSC mobilization efficiency in rats pretreated with CoCl Furthermore, we identified and compared the multilineage differentiation capacities of MSCs derived from bone marrow (BM-MSCs) and mobilized peripheral blood (PB-MSCs). The results indicated that PB-MSCs exhibited higher osteogenic potential and lower adipogenic differentiation as compared with BM-MSCs. The findings may inform studies investigating mechanisms of the regulation of MSC mobilization and can aid in the development of clinically useful therapeutic agents.
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