scholarly journals Biological Associations and Clinical Impact of Differential Expression of the Pre-Mir-29a/b-1 and Pre-Mir-29b-2/C Clusters in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5110-5110
Author(s):  
Florian Ramdohr ◽  
Marius Bill ◽  
Madlen Jentzsch ◽  
Karoline Schubert ◽  
Juliane Grimm ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Differential Expression ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Clinical Impact ◽  
High Expression ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Expression levels of miR-29 family members (i.e. miR-29a, miR-29b, & miR-29c) are deregulated in various neoplastic diseases, including acute myeloid leukemia (AML), known to affect DNA-methylation profiles by targeting epigenetic modifiers, & have been shown to be important for normal hematopoietic stem cell function. Mir-29 is organized in two distinctively regulated bi-cistronic clusters: the miR-29a/b-1 cluster & the miR-29b-2/c cluster. Here we evaluated the biological associations & clinical impact of the differential expression of pre-miR-29a/b-1 & pre-miR-29b-2/c clusters in AML. We analysed121 AML patients (pts) (median age 63 years [y], range 37-75 y) who have been consolidated with hematopoietic stem cell transplantation following non-myeloablative conditioning (nma-HCT; Fludarabin 30 mg/m2 on day -4 till -2 & 2 Gy total body irradiation) between 2000 & 2014 with pretreatment bone marrow material (BM) available. Disease status at nma-HCT was first (CR1 62%) or second complete remission (CR2 18%) or CR with incomplete peripheral recovery (CRi 20%). The mutation status (mut) of the ASXL1, CEBPA, DNMT3A IDH1, IDH2, NPM1, & TP53 gene & the FLT3-ITD & EVI1 expressionstatusas well as common surface marker expressions were assessed at diagnosis. European LeukemiaNet (ELN) classification was favorable (25%), intermediate-I (23%), intermediate-II (21%), adverse (27%) or unknown (4%). Pretreatment pre-miR-29a/b-1 & pre-miR-29b-2/c clusters expressionin bone marrow (BM)was measured by quantitative reverse transcription polymerase chain reaction & normalized to 18S. The median normalized gene expression defined high & low pre-miR-29a/b-1 & pre-miR-29b-2/c clusterexpressers. Median follow-up was 4.4y for pts alive. At diagnosis a high pre-miR-29a/b-1 expression did not associate with clinical characteristics. High pre-miR-29a/b-1 expressers were less likely to be TP53 mut (p=.01). Pts with high pre-miR-29b-2/c expression at diagnosis had higher BM blast counts (p=.01), were more likely to have a normal cytogenetics (CN, p=.03) & were less likely to be TP53 (p=.004) or ASXL1 mutated (p=.03). When we combined the expression status information of the two miR-29 clusters we found that AML blasts of pts with high expression of both clusters were less likely to be CD34 (p=.05) or CD117 (p=.04) positive & more likely to be CD11b positive (p=.05). These pts more often had CN-AML (p=.04) & better ELN genetic risk (p=.03). High expressers of both miR-29 clusters were also more likely to be DNMT3A mut (p=.01) & less likely to be EVI1 positive (p=.007). Noteworthy, none of the pts with high expression of both clusters had a TP53 (p=.16) or ASXL1 mutation (p=.08). Pts with a high expression of both miR-29 clustershad a significant longer relapse free survival (RFS, p=.01, Figure 1a) & overall survival (OS, p=.03) compared to pts with low expression of one or both miR-29 clusters. In conclusion, high expression of pre-miR-29a/b-1 & pre-miR-29b-2/c associated with different clinical & genetic characteristic at AML diagnosis. High expressers of both clusters were more often DNMT3A mutated, a gene targeted by miR-29. Furthermore, none of these patients harbored TP53 mutations, a gene known to be indirectly activated by miR-29 family members. These findings provide new insights into the miR-29 associated AML biology, which may contribute to the observed impact on AML pts outcomes. While we observed a trend for better survival for each miR-29 cluster, pts with high expression of the pre-miR-29a/b-1 & the pre-miR-29b-2/c clusterhad significantly longer RFS & OS. Figure 1 Figure 1. Disclosures Poenisch: Mundipharma: Research Funding.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation for Children and Adolescents with Acute Myeloid Leukemia in Brazil: A Multicentric Retrospective Study

2020 ◽  
Vol 29 ◽  
pp. 096368972094917
Author(s):  
Ana Luiza de Melo Rodrigues ◽  
Carmem Bonfim ◽  
Adriana Seber ◽  
Vergilio Antonio Rensi Colturato ◽  
Victor Gottardello Zecchin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Acute Myeloid

The survival rates of children with high-risk acute myeloid leukemia (AML) treated with hematopoietic stem cell transplant (HSCT) range from 60% to 70% in high-income countries. The corresponding rate for Brazilian children with AML who undergo HSCT is unknown. We conducted a retrospective analysis of 114 children with AML who underwent HSCT between 2008 and 2012 at institutions participating in the Brazilian Pediatric Bone Marrow Transplant Working Group. At transplant, 38% of the children were in first complete remission (CR1), 37% were in CR2, and 25% were in CR3+ or had persistent disease. The donors included 49 matched-related, 59 matched-unrelated, and six haploidentical donors. The most frequent source of cells was bone marrow (69%), followed by the umbilical cord (19%) and peripheral blood (12%). The 4-year overall survival was 47% (95% confidence interval [CI] 30%–57%), and the 4-year progression-free survival was 40% (95% CI 30%–49%). Relapse occurred in 49 patients, at a median of 122 days after HSCT. There were 65 deaths: 40 related to AML, 19 to infection, and six to graft versus host disease. In conclusion, our study suggests that HSCT outcomes for children with AML in CR1 or CR2 are acceptable and that this should be considered in the overall treatment planning for children with AML in Brazil. Therapeutic standardization through the adoption of multicentric protocols and appropriate supportive care treatment will have a significant impact on the results of HSCT for AML in Brazil and possibly in other countries with limited resources.

scholarly journals Hematopoietic Stem Cell Transplantation for Pediatric Acute Myeloid Leukemia - SBTMO/SOPOBE 2020 Consensus Guidelines

JBMTCT ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 139
Author(s):  
Ana Luiza De Melo Rodrigues ◽  
Victor Gottardello Zecchin ◽  
Maria Lúcia de Martino Lee ◽  
Antonella Adriana Zanette ◽  
Adriana Seber ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
Hematopoietic Stem Cell ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Brazilian Society ◽  
Acute Myeloid

Acute myeloid leukemia (AML) represents 15%–20% of acute leukemias in children, and the risk of treatment failure is based on genetic risk and response to therapy1-4. Although the initial remission rate exceeds 90%, more than 30-40% of children with AML die of refractory/relapsed disease or treatment-related toxicity5. The best therapeutic results are achieved by integrating intensive chemotherapy, optimal supportive care, and hematopoietic stem cell transplant (HSCT) adapted to each patient’s risk of relapse6–9. In 2020, the Brazilian Group for Pediatric Bone Marrow Transplantation of the Brazilian Society of Bone Marrow Transplantation and Cellular Therapy (SBTMO) and the Brazilian Society for Pediatric Oncology (SOBOPE) convened a task force to provide general guidance on HSCT for childhood AML to provide evidence-based guidance for the appropriate management of this disease.

A NUP98-HOXD13 Fusion Gene Induces a Transplantable Myelodysplastic Syndrome in Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 401-401
Author(s):  
Yang Jo Chung ◽  
Chul Won Choi ◽  
Christopher Slape ◽  
Terry Fry ◽  
Peter D. Aplan
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Acute Myeloid

Abstract The myelodysplastic syndromes (MDSs) are a group of hematologic stem cell disorders characterized by ineffective hematopoiesis and dysplasia. A large number of chromosomal aberrations including deletions, amplifications, inversions, and translocations, some of which involve the NUP98 gene, have been associated with MDS. Recently an MDS mouse model expressing a NUP98-HOXD13 (NHD13) fusion gene was developed, which faithfully recapitulates all of the key features of MDS. Although it is well-established that acute myeloid leukemia (AML) is transplantable, there is no evidence that MDS is a transplantable condition. Therefore, in order to develop evidence for MDS as a hematopoietic stem cell (HSC) disease, we attempted to transfer MDS to normal recipients through bone marrow transplantation (BMT). All the recipients transplanted with bone marrow (BM) cells from NHD13 mice with MDS showed anemia, leukopenia, lymphopenia, and neutropenia when compared to recipients of wild-type (WT) littermates. The homing efficiency of the NHD13 primitive progenitor cells (Lineage negative [Lin−], Sca-1+) was about 2 fold higher than WT, and there was no significant difference in BM cellularity between the recipients of NHD13 and WT BM, indicating that the NHD13 recipients had ineffective hematopoiesis. These phenomena were reproduced in secondary recipients using primary recipients of NHD13 BM as donor mice. In secondary transplantation assays, 3 out of 5 recipients developed acute myeloid leukemia (AML) at 16 weeks post-transplantation. Morphological features of MDS, including nuclear-cytoplasmic asynchrony, binucleate cells, hypersegmented neutrophils, and giant platelets were detected in BM and peripheral blood of NHD13 donor, primary and secondary recipients by cytospin preparations. In competitive repopulation assays, mice transplanted with equal numbers of WT and NHD13 BM cells showed a decreased percentage of NHD13 cells in the peripheral blood, but an increased percentage of NHD13 cells in the BM, again providing evidence of ineffective hematopoiesis of the NHD13 cells. The transplantation of lineage depleted cells from BM has shown that the transplantable cells for MDS reside in the Lin− population of NHD13 BM. These findings demonstrate that MDS can be transferred to healthy recipients by BMT, supporting the concept that MDS originates in a transplantable multilineage hematopoietic stem cell.

scholarly journals Establishment of a Novel CD34+ Hematopoietic Stem Cell-derived Xenograft Model of Hyperleukocytic Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Yanxia Jin ◽  
Ziyi Luo ◽  
Linlu Ma ◽  
Yanling Chen ◽  
Yujia Zheng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Survival Time ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Xenograft Model ◽  
Hematopoietic Stem ◽  
Pdx Model ◽  
Acute Myeloid

Abstract BackgroundHyperleukocytic acute myeloid leukemia (HLL) with high early mortality is difficult to therapy. The related research on HLL is still in its infancy, and the establishment of a patient derived xenograft (PDX) model of HLL has not been fully reported, especially the CD34+ hematopoietic stem cell-derived xenograft model of HLL. MethodsUsing the routine blood examination, smear analysis and bone marrow biopsy, flow cytometry, mutation analysis to evaluate the establishment of HLL model. And the correlation between the survival time in mice and in patients was analyzed by a linear regression model with variable selection “entered” with SPSS software.ResultsOur findings demonstrated that the leukocyte counts reached up to 37.35Í109/l, and the immunophenotypes of hCD45+, hCD15+ and hCD33+ cells were detected in peripheral blood (PB) and bone marrow (BM) after inoculation with cells derived from PB for establishment of the HLL PDX model. The same results were demonstrated after inoculation with cells derived from BM of the patient. For the CD34+ hematopoietic stem cell derived xenograft model, the CD34+ hematopoietic stem cells more severely infiltrated the BM, liver and spleen. More importantly, human WT1 and NRAS mutants were detected in the liver, spleen and BM of the mouse. By performing a comparative analysis of multiple experiments, we found that mice receiving a higher irradiation dose of 2.5 Gy and higher injected cell counts derived from PB exhibited a shorter survival time. Furthermore, the constructed model mice injected with NRAS, DNMT3A, FLT3, or NMPM1 gene mutations had shorter survival times. The correlation analysis showed that the survival time in mice was significantly related with the survival status of the enrolled patients. ConclusionsWe successfully established a novel CD34+ hematopoietic stem cell-derived xenograft model of HLL, which shows great promise for mechanistic research, drug screening, individualized therapy, clinical efficacy assessment and precision medicine in HLL.

Construction of a Novel CD34+ Hematopoietic Stem Cell Derived Xenograft Model of Human Hyperleukocytic Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Yanxia Jin ◽  
Yanling Chen ◽  
Yujia Zheng ◽  
Fuling Zhou
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Xenograft Model ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Leukocyte Counts ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is an abnormal clonal proliferative disease of hematopoietic progenitors in the bone marrow, which is the most common malignant disease in the blood system. Hyperleukocytic leukemia (HLL) is one of the high-risk types and commonly defined as peripheral blood leukocyte counts exceeding 50-100×109/l. The patients with hyperleukocytic acute myeloid leukemia (HL-AML) usually suffer from poor prognosis due to low responsiveness to initial chemotherapeutic agents, so these patients have higher mortality with life-threatening complication than those without hyperleukocytosis. However, there is no available patient derived xenograft model (PDX) in HL-AML, especially the CD34+ hematopoietic stem cell derived xenograft model of human HL-AML. In this study, firstly, the primary HL-AML cells were collected and separated from the patients who underwent leukapheresis by using Fresenius COM.TEC machine, and the CD34+ hematopoietic stem cells were isolated from primary HL-AML cells using magnetic beads. Then, the NOD-SCID-IL2rγnull (B-NSG) mice were treated with 1.5 Gy χ-ray for total body irradiation at day 0, and intravenously injected with isolated 1.5 × 107 HLL cells or 1.5 × 106 CD34+ cells mixed with G-CSF within 24 h of irradiation. After inoculation, the blood smear, bone marrow smear, immunophenotyping and histopathology were used to test whether the model was successfully constructed. For construction of hematopoietic stem cell derived xenograft model in HL-AML, at day 9, the immunophenotypes of hCD45+ and hCD34+ cells were found and had higher ratios in CD34+ group than HLL group in peripheral blood, which suggested the model was successfully established. The body weight of mice in CD34+ group were decreased faster than the HLL group due to severe tumor load and the leukocyte counts were increased higher than the correspondent HLL group after cell inoculation. In CD34+ group, the blood routine examination had changed, especially the WBC counts and PLT counts. On the 25th day, leukemic cells were found by the blood smears analysis and detected by flow cytometry, and which were more obviously found in bone marrow, and the immunophenotypes ratio of hCD45+ and hCD34+ were increased in CD34+ group. A lot of CD34+ cells were infiltrated into bone marrow, liver and spleen tissues on the 25th day that detected by histopathological analysis, which indicated that the more obviously model construction using hematopoietic stem cell derived leukemic cell. In a conclusion, we successfully constructed a novel CD34+ hematopoietic stem cells derived animal model of human hyperleukocytic AML, which is available for mechanism research and drug treatment. Disclosures No relevant conflicts of interest to declare.

scholarly journals Magnesium levels and outcome after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

2020 ◽  
Author(s):  
Linus Angenendt ◽  
Isabel Hilgefort ◽  
Jan-Henrik Mikesch ◽  
Bernhard Schlüter ◽  
Wolfgang E. Berdel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Epstein Barr Virus Infection ◽  
Hematopoietic Stem ◽  
Acute Myeloid

AbstractLow intake of magnesium has been associated with the occurrence of lymphomas and decreased magnesium levels suppress the cytotoxic function of T cells and natural killer cells in patients with “X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia” (XMEN) syndrome. These cell types are also important mediators of immune-mediated effects after allogeneic hematopoietic stem cell transplantation. Here, we show that high posttransplant magnesium levels independently associate with a lower incidence of relapse, a higher risk of acute graft-versus-host disease, and a higher non-relapse mortality in 368 patients with acute myeloid leukemia from our center. Magnesium serum levels might impact on donor-cell-mediated immune responses in acute myeloid leukemia.

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