Tracking of Leukemic and Pre-leukemic Clones in AML
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB41177 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR4843980.fastq.gz | Fastqsanger.gz | |||
| ERR4843980_1.fastq.gz | Fastqsanger.gz | |||
| ERR4843980_2.fastq.gz | Fastqsanger.gz | |||
| ERR4843990.fastq.gz | Fastqsanger.gz | |||
| ERR4843990_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 84 |
Similar Datasets
Project description:Germline RUNX1 mutations are found in familial platelet disorders with predisposition to acute myelogenous leukemia (FPD/AML). This very rare disease is characterized by thrombocytopenia, platelet dysfunction and a 35% lifetime risk of developing MDS/AML and in rare cases also T-ALL. Here, we focus on a case of a man with a familial history of RUNX1 R174Q mutation who developed at the age of 42 years an EGIL T2-ALL and two years after remission an AML-M0. To investigate whether initial and relapsed leukemic blasts originated from the same clone, we performed CGH array and WES on both blasts populations. In both T2-ALL and AML-M0 samples, CGH array revealed loss of 1p36.32-23 and 17q11.2 and nine other small deletions. Both AML-M0 and T2-ALL demonstrated clonal rearrangements of both TCR (V9-J1-1) and TCR (D2-J1 and D2-J3). 18 genes were found by WES to be mutated in the original clone at a frequency of more than 40%. Additional variants were identified only in T2-ALL or in AML-M0 evoking the existence of a common original clone. MiSeq technology performed on peripheral blood-derived CD34+ cells five years prior T2-ALL development revealed only missense TET2 P1962T mutation at a frequency of 1% suggesting that this mutation in association with germline RUNX1 R174Q mutation led to amplification of a hematopoietic clone susceptible to acquire other transforming alterations. Identification of clonal hematopoiesis with acquired mutations at low frequency in hematopoietic progenitors before leukemia development could clearly serve as a marker of pre-leukemic state and might be helpful in patient care.
2017-07-05 | E-MTAB-4679 | biostudies-arrayexpress
Project description:Germline RUNX1 mutations are found in familial platelet disorders with predisposition to acute myelogenous leukemia (FPD/AML). This very rare disease is characterized by thrombocytopenia, platelet dysfunction and a 35% lifetime risk of developing MDS/AML and in rare cases also T-ALL. Here, we focus on a case of a man with a familial history of RUNX1 R174Q mutation who developed at the age of 42 years an EGIL T2-ALL and, two years after remission, an AML-M0. To investigate whether initial and relapsed leukemic blasts originated from the same clone, we performed CGH array and WES on both blasts populations. In both T2-ALL and AML-M0 samples, CGH array revealed loss of 1p36.32-23 and 17q11.2 and nine other small deletions. Both AML-M0 and T2-ALL blasts demonstrated clonal rearrangements of both TCRγ (Vγ9-Jγ1-1) and TCRδ (Dδ2-Jδ1 and Dδ2-Jδ3). 18 genes were found by WES to be mutated in both blasts at a frequency of more than 40%. Additional variants were identified only in T2-ALL or in AML-M0 evoking the existence of a common original clone, which gave rise to subclonal populations. MiSeq technology performed on peripheral blood-derived CD34+ cells five years prior T2-ALL development revealed only missense TET2 P1962T mutation at a frequency of 1% (which reaches a frequency of 50 % in fully transformed leukemic clone) suggesting that this mutation in association with germline RUNX1 R174Q mutation led to amplification of a hematopoietic clone susceptible to acquire other transforming alterations. Identification of clonal hematopoiesis with acquired mutations at low frequency in hematopoietic progenitors before leukemia development could clearly serve as a marker of pre-leukemic state and be helpful in patient care.
2017-06-29 | E-MTAB-4623 | biostudies-arrayexpress
Project description:The tracking of leukemic clones in acute myeloid leukemic promisses deeper insights into disease development and therapeutic options. We therefore established a fluorescent genetic barcoding (FGB) labeling approach that allows for flow cytomtric tracking of color-coded clones in vitro and in vivo. In Hoxa9 and Meis1 (H9M) dependent murine AML, we tracked the growth behavior of 24 clones in parallel and enriched for pre-leukemic clones as well as their de novo expanded counterparts and stably expanded clones from leukemic mice by fluorescence-activated cell sorting. These samples were subjected toRNA sequencing for the assessment of transcriptional changes underlying clonal maintenance and expansion.
2022-12-28 | GSE198371 | GEO
Project description:<p>Acute myeloid leukemia is an aggressive clonal malignancy of the bone marrow that is the direct result of sequential acquisition of mutations in a single lineage of cells. In this study, we investigate a model in which this mutational acquisition occurs serially in long-lived self-renewing hematopoietic stem cells eventually resulting in frank acute myeloid leukemia. Coding mutations in multiple AML patients were identified using exome sequencing followed by sanger sequencing validation. The level of these mutations was then assessed in residual hematopoietic stem cells from each patient using targeted deep sequencing. These population-level estimates of mutant allele burden were then validated in single cell assays targeted to the identified mutations. This allowed for determination of the order of acquisition of the mutations that preceded the development of the leukemia. The results of this study identify pre-leukemic hematopoietic stem cell clones that could contribute to patient relapse and outcome.</p>
| phs000549 | dbGaP
Project description:To understand the pathogenesis of DNMT3A in acute monocytic leukemia (AML-M5), we identified genes that are expressed differently in leukemia cells from AML-M5 patients collected at diagnosis with DNMT3A mutations (6 cases) compared to those without the mutations (4 cases). Differences of expression level were observed in 889 out of 20,723 (4.3%) annotated genes by using Affymetrix microarray with 469 genes upregulated and 420 genes downregulated. Leukemia cells in bone marrow of acute monocytic leukemia patients were collected at diagnosis for RNA extraction and hybridization on Affymetrix microarrays. 6 cases of AML-M5 samples with DNMT3A mutations and 4 cases of AML-M5 samples wihtout DNMT3A mutations were used.
2011-02-12 | E-GEOD-27187 | biostudies-arrayexpress
Project description:Leukemogenesis is a stepwise progression from mutated, pre-neoplastic hematopoietic stem cells (HSCs) to full-blown leukemia. Our ability to prevent or treat de novo and secondary acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption that is central to this process, including improper histone methylation. We performed a comprehensive analysis of 16 histone H3 genes in 434 primary acute myeloid leukemia (AML) samples and identified mutations in adult and pediatric cases (1.6%), with a higher incidence in secondary AML (s-AML) (9%). These included four novel amino acid substitutions (Q69H, A26P, R2Q and R8H) as well as K27M and K27I in H3.1 and H3.3 genes. These mutations are important early events in leukemogenesis as they were observed in pre-leukemic HSCs in two cases and were in the major clones in every sample. Consistent with a role in pre-leukemic HSC clonal expansion, the mutant histones increased functional human HSC frequency and altered differentiation along the erythroid and myeloid lineages, with activity dependent on the specific mutation (K27M, K27I and Q69H). In established human leukemia, the K27M/I mutant histones amplified leukemic aggressiveness, with increased proliferation, expansion of leukemic progenitor and blast cells, and superior competitiveness in vivo. This was associated with increased expression in genes involved in erythrocyte and myeloid differentiation, correlated with a corresponding decrease in histone H3 K27 tri-methylation and increase in K27 acetylation. While histone mutations can co-occur with alterations in RUNX1, we observed that the functional impact of histone mutations is independent of RUNX1 mutations. Taken together, these data establish the involvement of H3 mutations as early drivers of pre-leukemic HSC expansion and leukemogenesis.
2019-04-05 | GSE122273 | GEO
Project description:Comparison of pre-leukemic and leukemic H9M AML clones from murine splenocytes
| PRJNA814710 | ENA
Project description:Severe congenital neutropenia (CN) is a pre-leukemia syndrome that, in the majority of patients, is caused by heterogeneous ELANE mutations encoding neutrophil elastase (NE). To study leukemogenesis associated with CN we generated CN and CN/AML patient-specific induced pluripotent stem cells (iPSCs). Additional mutations in leukemia-relevant genes, CSF3R and RUNX1, were introduced using CRISPR/Cas9 gene-editing. Consequently, we performed in vitro embryoid body (EB)-based hematopoietic and myeloid differentiation of generated iPSC lines. On day 14-17 of EB-based differentiation, iPSC-derived CD45+CD34+ cells were harvested and mRNA was isolated using RNeasy Mini- or Micro Kit (Qiagen). Sequencing libraries were prepared using the TruSeq RNA Sample Prep Kit (Illumina). Poly (A) selected single-read and pair-read sequencing libraries were sequenced on the Illumina platform in order to compare the transcriptomes of CN and CN/AML iPSCs-derived HSPCs from 2 CN/AML patients. Next, we identified that BAALC knockout resulted in a dramatic induction of granulocytic differentiation and a significant reduction in proliferation of CN/AML iPSC-derived HSPCs. To identify BAALC-dependent leukemia-associated gene expression, we compared the transcriptomes of CN/AML iPSCs before and after BAALC KO using a similar approach described above for CN and CN/AML iPSCs-derived HSPCs.
2021-03-08 | E-MTAB-10162 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is a heterogenous and complex blood cancer, with poor prognosis and wide-raging complications. Early identification and prediction of complications is vital for effective disease management. We performed longitudinal plasma profiling of 26 AML patients during chemotherapy-induced neutropenia, to explore the role of plasma proteins in evaluating the severity and prognosis of AML. We found that the majority of proteins varied in levels between patients, while remaining relatively stable within patients. Inflammatory proteins were significantly correlated with fever and its complications, and may serve as a useful biomarker panel to monitor AML patients during disease progression.
2024-11-06 | PXD040526 | Pride
Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, often characterized by poor prognosis following standard induction therapy. The DNA methyltransferase inhibitor decitabine (DAC) is an alternative to intensive chemotherapy in elderly and relapsed/refractory AML patients. Despite some efficacy, DAC monotherapy does not promote complete remission and overall survival rates are very poor. Therefore, novel therapeutic regimens for AML are warranted. CD105 (endoglin), a receptor for the TGF-β superfamily, is expressed in various hematopoietic malignancies, including AML in which high expression correlates with poor prognosis. We have recently demonstrated that targeting CD105+ AML blasts with the TRC105 monoclonal antibody abrogates leukemogenesis in vivo. Based on these encouraging findings, here we investigated whether TRC105 in combination with DAC could represent a novel therapeutic option to treat relapsed/refractory AML. Treatment of leukemic mice with DAC in combination with TRC105 resulted in superior survival and significant reduction of leukemia burden in the bone marrow (BM) of AML xenografts compared to DAC monotherapy. To determine if TRC105 anti-leukemogenic effect is mediated by NK cells, we performed in vitro and in vivo studies. In the latter, we tested TRC105 in the context of NK depletion by injecting mice with an antibody to CD122. TRC105 treatment resulted in comparable reduction of leukemia burden in xenografts regardless of NK depletion, demonstrating that the anti-leukemogenic effect of TRC105 in AML is independent of NK cells. Altogether, our findings provide proof-of-principle for the clinical evaluation of TRC105 in combination with DAC in AML patients.
2020-10-27 | GSE147503 | GEO