9bc5e598-a31e-4224-9748-c73151044d05 - samples
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ABSTRACT:
PROVIDER: EGAD00001007793 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL
2021-12-31 | GSE178237 | GEO
Project description:Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL
2021-12-31 | GSE178238 | GEO
Project description:Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL
| EGAS00001005403 | EGA
Project description:The hematopoietic master regulator RUNX1 is frequently mutated in myeloid and lymphoid malignancies. Analyses of RUNX1 mutations across hematopoietic tissues revealed frequent mutations outside of the N-terminal DNA binding domain. The vast majority of these C-terminal mutations were found to be nonsense and frameshifts resulting in truncated protein products predicted to escape nonsense mediated decay pathways. We modeled this class of truncation mutation using the pathogenic RUNX1 R320* mutation found in both germline and sporadic hematological disease. Homozygous knock-in of RUNX1 R320* in K562 leukemia cells resulted in a megakaryocytic differentiation block and DNA damage sensitivity phenotypes. Gene expression analysis demonstrated that RUNX1 R320* dysregulated unique gene sets when compared to RUNX1 knockdown in addition to shared genes related to megakaryocyte and platelet function. DNA binding across the genome was examined between RUNX1 wild-type and RUNX1 R320* through ChIP-seq, revealing that RUNX1 R320* differential binding was most enriched at enhancer regions. To detect RUNX1 R320* dysregulated enhancer-promoter (E-P) connections we performed GRID-seq and uncovered extensive remodeling of E-P interactions genome-wide in RUNX1 R320* cells. Furthermore, we uncovered a novel role for FOXK2 at RUNX1 regulated enhancers. Analysis of the well-studied MYC enhancer region demonstrated cooperation between RUNX1 R320* and FOXK2 at hematopoietic MYC enhancers NDME and BENC resulting in the significant upregulation of the MYC oncogene. In conclusion, the truncation of RUNX1 results in impaired megakaryocytic differentiation, unique transcriptional alterations, and remodeling of enhancer-promoter connections in cooperation with FOXK2, together contributing to leukemogenesis.
2024-05-29 | GSE236641 | GEO
Project description:The hematopoietic master regulator RUNX1 is frequently mutated in myeloid and lymphoid malignancies. Analyses of RUNX1 mutations across hematopoietic tissues revealed frequent mutations outside of the N-terminal DNA binding domain. The vast majority of these C-terminal mutations were found to be nonsense and frameshifts resulting in truncated protein products predicted to escape nonsense mediated decay pathways. We modeled this class of truncation mutation using the pathogenic RUNX1 R320* mutation found in both germline and sporadic hematological disease. Homozygous knock-in of RUNX1 R320* in K562 leukemia cells resulted in a megakaryocytic differentiation block and DNA damage sensitivity phenotypes. Gene expression analysis demonstrated that RUNX1 R320* dysregulated unique gene sets when compared to RUNX1 knockdown in addition to shared genes related to megakaryocyte and platelet function. DNA binding across the genome was examined between RUNX1 wild-type and RUNX1 R320* through ChIP-seq, revealing that RUNX1 R320* differential binding was most enriched at enhancer regions. To detect RUNX1 R320* dysregulated enhancer-promoter (E-P) connections we performed GRID-seq and uncovered extensive remodeling of E-P interactions genome-wide in RUNX1 R320* cells. Furthermore, we uncovered a novel role for FOXK2 at RUNX1 regulated enhancers. Analysis of the well-studied MYC enhancer region demonstrated cooperation between RUNX1 R320* and FOXK2 at hematopoietic MYC enhancers NDME and BENC resulting in the significant upregulation of the MYC oncogene. In conclusion, the truncation of RUNX1 results in impaired megakaryocytic differentiation, unique transcriptional alterations, and remodeling of enhancer-promoter connections in cooperation with FOXK2, together contributing to leukemogenesis.
2024-05-29 | GSE236640 | GEO
Project description:The hematopoietic master regulator RUNX1 is frequently mutated in myeloid and lymphoid malignancies. Analyses of RUNX1 mutations across hematopoietic tissues revealed frequent mutations outside of the N-terminal DNA binding domain. The vast majority of these C-terminal mutations were found to be nonsense and frameshifts resulting in truncated protein products predicted to escape nonsense mediated decay pathways. We modeled this class of truncation mutation using the pathogenic RUNX1 R320* mutation found in both germline and sporadic hematological disease. Homozygous knock-in of RUNX1 R320* in K562 leukemia cells resulted in a megakaryocytic differentiation block and DNA damage sensitivity phenotypes. Gene expression analysis demonstrated that RUNX1 R320* dysregulated unique gene sets when compared to RUNX1 knockdown in addition to shared genes related to megakaryocyte and platelet function. DNA binding across the genome was examined between RUNX1 wild-type and RUNX1 R320* through ChIP-seq, revealing that RUNX1 R320* differential binding was most enriched at enhancer regions. To detect RUNX1 R320* dysregulated enhancer-promoter (E-P) connections we performed GRID-seq and uncovered extensive remodeling of E-P interactions genome-wide in RUNX1 R320* cells. Furthermore, we uncovered a novel role for FOXK2 at RUNX1 regulated enhancers. Analysis of the well-studied MYC enhancer region demonstrated cooperation between RUNX1 R320* and FOXK2 at hematopoietic MYC enhancers NDME and BENC resulting in the significant upregulation of the MYC oncogene. In conclusion, the truncation of RUNX1 results in impaired megakaryocytic differentiation, unique transcriptional alterations, and remodeling of enhancer-promoter connections in cooperation with FOXK2, together contributing to leukemogenesis.
2024-05-29 | GSE236638 | GEO
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:Ficolled AML-M0 sample gene expression profiles on Affymetrix HGU133Plus2.0 GeneChips. Acute myeloid leukemia (AML) classified as FAB-M0 is defined as a subtype with minimally differentiated morphology. Here we investigated by gene expression (GEP) profiling whether AML-M0 cases should be considered as one or more unique molecular subgroups that discriminates them from other AML patients. By applying GEP and subsequent unsupervised analysis of 35 AML-M0 samples and 253 previously reported AML cases, we demonstrate that AML-M0 cases express a unique signature. Hematological transcription regulators such as CEBPA, CEBPD, PU.1 and ETV6 and the differentiation associated gene MPO appeared strongly down-regulated, in line with the very primitive state of this type of leukemia. Moreover, AML M0 cases appeared to have a strong positive correlation with a previously defined immature AML subgroup with adverse prognosis. AML-M0 leukemias frequently carry loss-of-function RUNX-1 mutation and unsupervised analyses revealed a striking distinction between cases with and without mutations. RUNX1 mutant AML-M0 samples showed a distinct up-regulation of B-cell-related genes, e.g. members of the B-cell receptor complex, transcriptions regulators RUNX3, ETS2, IRF8 or PRDM1 and major histocompatibility complex class II genes. Importantly, expression of one single gene, i.e. BLNK, enabled prediction of RUNX1 mutations in AML-M0 with high accuracy. We propose that RUNX1 mutations in this subgroup of AML cause lineage infidelity, leading to aberrant co-expression of myeloid and B-lymphoid genes in the same cells. Experiment Overall Design: 35 samples
2009-07-18 | E-GEOD-17061 | biostudies-arrayexpress
Project description:Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemia stage in which B-cell precursors display self-renewal ability, initiating precursor B-ALL that resembles PAX5 P80R or Ph-like human leukemia. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving both JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are novel treatment avenues for IL-7R-related cases. Our model, a unique resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.
2021-11-02 | PXD017147 | Pride