Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide clues as to their pathogenesis and therapeutic targeting.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229948 | GEO | 2023/11/21
REPOSITORIES: GEO
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Project description:PHF6 mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Our comprehensive genomic analyses focused on three main findings. Firstly, we revealed a different pattern of genes correlating with PHF6MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 were co-mutated with PHF6. In contrast, female cases revealed co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6MT. Next, proteomics analysis revealed a direct interaction between PHF6 and the pioneer transcription factor RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrated a negative prognostic role of PHF6MT, especially in association with RUNX1. The negative effects on survival were additive as PHF6MT cases with RUNX1 mutations had worse outcomes when compared to cases carrying single mutation or wild-type.
2023-11-21 | PXD042441 | Pride
Project description:Genes encoding subunits of SWI/SNF chromatin remodeling complexes are mutated in nearly 25% of cancers. The SWI/SNF subunit SMARCB1 is the driving mutation in nearly all cases of rhabdoid tumor (RT), highly malignant cancers of childhood. While loss of SMARCB1 drives cancer, its absence also creates unique dependencies, which can illuminate mechanism and reveal potential therapeutic vulnerabilities. To identify such dependencies we undertook a genome-scale CRISPR screen comparing RT cell lines to 800 other cancer lines. We identified PHF6 as specifically essential for RT cell survival. Germline mutations in both SMARCB1 and PHF6 cause Coffin-Siris syndrome, and somatic mutations in PHF6 or SWI/SNF occur in T-ALL, suggesting a mechanistic link. We establish that PHF6 co-localizes with residual SWI/SNF complexes at active promoters and enhancers. We find that PHF6 is specifically required for H3K14ac accumulation immediately downstream of active promoters and for release of paused Pol II. Collectively, our work identifies novel integrated roles for PHF6 in chromatin and Pol II regulation, establishes a mechanistic basis for dependence upon PHF6 in RT, and reveals a novel potential therapeutic vulnerability in RT.
2024-06-07 | GSE269349 | GEO
Project description:Genes encoding subunits of SWI/SNF chromatin remodeling complexes are mutated in nearly 25% of cancers. The SWI/SNF subunit SMARCB1 is the driving mutation in nearly all cases of rhabdoid tumor (RT), highly malignant cancers of childhood. While loss of SMARCB1 drives cancer, its absence also creates unique dependencies, which can illuminate mechanism and reveal potential therapeutic vulnerabilities. To identify such dependencies we undertook a genome-scale CRISPR screen comparing RT cell lines to 800 other cancer lines. We identified PHF6 as specifically essential for RT cell survival. Germline mutations in both SMARCB1 and PHF6 cause Coffin-Siris syndrome, and somatic mutations in PHF6 or SWI/SNF occur in T-ALL, suggesting a mechanistic link. We establish that PHF6 co-localizes with residual SWI/SNF complexes at active promoters and enhancers. We find that PHF6 is specifically required for H3K14ac accumulation immediately downstream of active promoters and for release of paused Pol II. Collectively, our work identifies novel integrated roles for PHF6 in chromatin and Pol II regulation, establishes a mechanistic basis for dependence upon PHF6 in RT, and reveals a novel potential therapeutic vulnerability in RT.
2024-06-07 | GSE180483 | GEO
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:PURPOSE: To evaluate frequency, biological features and clinical relevance of RUNX1 mutations in acute myeloid leukemia (AML). PATIENTS AND METHODS: Diagnostic samples from 945 patients (18 to 60 years) were analyzed for RUNX1 mutations. In a subset of cases (n=269) microarray gene expression analysis was performed. RESULTS: Fifty-nine RUNX1 mutations were identified in 53 of 945 (5.6%) cases, predominantly in exons 3 (n=11), 4 (n=10) and 8 (n=23). RUNX1 mutations clustered in the intermediate-risk cytogenetic group (46/640, 7.2%; cytogenetically normal, 34/538, 6.3%), they were less frequent in adverse-risk cytogenetics (5/109, 4.6%), and absent in core-binding-factor AML (0/77) and acute promyelocytic leukemia (0/61); RUNX1 mutations were associated with MLL-partial tandem duplications (p=0.0007) and IDH1/IDH2 mutations (p=0.03), inversely correlated with NPM1 (p<0.0001) and in trend with CEBPA (p=0.10) mutations. RUNX1 mutations were characterized by a distinct gene expression pattern; this RUNX1 mutation-derived signature was not exclusive for the mutation, but also included mostly adverse-risk AML [eg, 7q-, -7, inv(3) or t(3;3)]. RUNX1 mutations predicted for resistance to chemotherapy (rates of refractory disease 30% and 19%, p=0.047, for RUNX1-mutated and wildtype patients, respectively), as well as inferior event-free survival (EFS; p<0.0001), relapse-free survival (RFS, p=0.022), and overall survival (p=0.051). In multivariable analysis, RUNX1 mutations were an independent prognostic marker for shorter EFS (p=0.007). Explorative subgroup analysis revealed that allogeneic hematopoietic stem cell transplantation had a favorable impact on RFS in RUNX1-mutated patients (p<0.0001). CONCLUSION: AML with RUNX1 mutations exhibit distinct biological properties and are associated with resistance to therapy and inferior outcome. A total of 269 RNA samples derived from adult AML patients were provided by the German Austrian AML Study Group (AMLSG) [AMLSG trial AML HD98A (ClinicalTrials.gov Identifier: NCT00146120)]. Conventional cytogenetic banding, and FLT3, CEBPA and NPM1 mutational analysis were performed as previously described (Schlenk et al., N Engl J Med 2008). Detailed clinical, cytogenetic and molecular cytogenetic information are also provided in the supplementary information. Following enrichment, all samples contained at least 80% leukemic cells. Gene expression profiling (GEP) was performed as previously described (Bullinger et al., N Engl J Med 2004).
2010-12-31 | E-GEOD-23312 | biostudies-arrayexpress
Project description:PURPOSE: To evaluate frequency, biological features and clinical relevance of RUNX1 mutations in acute myeloid leukemia (AML). PATIENTS AND METHODS: Diagnostic samples from 945 patients (18 to 60 years) were analyzed for RUNX1 mutations. In a subset of cases (n=269) microarray gene expression analysis was performed. RESULTS: Fifty-nine RUNX1 mutations were identified in 53 of 945 (5.6%) cases, predominantly in exons 3 (n=11), 4 (n=10) and 8 (n=23). RUNX1 mutations clustered in the intermediate-risk cytogenetic group (46/640, 7.2%; cytogenetically normal, 34/538, 6.3%), they were less frequent in adverse-risk cytogenetics (5/109, 4.6%), and absent in core-binding-factor AML (0/77) and acute promyelocytic leukemia (0/61); RUNX1 mutations were associated with MLL-partial tandem duplications (p=0.0007) and IDH1/IDH2 mutations (p=0.03), inversely correlated with NPM1 (p<0.0001) and in trend with CEBPA (p=0.10) mutations. RUNX1 mutations were characterized by a distinct gene expression pattern; this RUNX1 mutation-derived signature was not exclusive for the mutation, but also included mostly adverse-risk AML [eg, 7q-, -7, inv(3) or t(3;3)]. RUNX1 mutations predicted for resistance to chemotherapy (rates of refractory disease 30% and 19%, p=0.047, for RUNX1-mutated and wildtype patients, respectively), as well as inferior event-free survival (EFS; p<0.0001), relapse-free survival (RFS, p=0.022), and overall survival (p=0.051). In multivariable analysis, RUNX1 mutations were an independent prognostic marker for shorter EFS (p=0.007). Explorative subgroup analysis revealed that allogeneic hematopoietic stem cell transplantation had a favorable impact on RFS in RUNX1-mutated patients (p<0.0001). CONCLUSION: AML with RUNX1 mutations exhibit distinct biological properties and are associated with resistance to therapy and inferior outcome.
2010-12-31 | GSE23312 | GEO
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.
2009-07-14 | GSE17061 | GEO
Project description:Background: Multiple autoantigens have been identified in membranous nephropathy (MN) by tissue-based proteomics. However, the antigenic targets of disease are unknown for >10% of MN and >50% of membranous lupus nephritis (MLN) cases. We identified multiple new targets in PLA2R-/THSD7A-/EXT-/NELL1-quadruple negative MN biopsies through mass spectrometry (MS) of immune complexes recovered from biopsy tissue of patients with MN. Methods: MN cases negative for PLA2R, THSD7A, EXT1/2, and NELL1 were identified from a biopsy database. Protein G immunoprecipitation was used to recover immune complexes from frozen biopsy tissue, followed by interrogation by mass spectrometry (MS). Potential antigens were confirmed through paraffin immunofluorescence of protein targets, followed by co-localization with IgG within immune deposits. Consecutive series of 165 cases of PLA2R-negative MN biopsies and 95 MLN biopsies was screened to determine the frequency for each potential antigen. Results: Seven protein targets were discovered within immune complexes from MN biopsies including FCN3, CD206, EEA1, SEZ6L2, NPR3, MST1, and VASN. Peptides from these proteins on MS were not enriched in PLA2R (n=86), THSD7A (n=64), NELL1 (n=64), or EXT1/2 (n=60) controls. Between 3-30 unique peptides were detected for each target. Frequencies of each antigen, determined by staining consecutive case series, were SEZ6L2 (1/165 idiopathic; 0/95 MLN), VASN (8/165 idiopathic; 2/95 MLN), EEA1 (6/165 idiopathic; 7/95 MLN), MST1 (6/165 idiopathic; 2/95 MLN), and FCN3 (0/165 idiopathic, 6/95 MLN), NPR3 and CD206 were positive in index cases. All cases showed co-localization of IgG within immune deposits. Conclusion: Seven novel protein targets were identified in MN and MLN.
2023-04-06 | PXD035853 | Pride
Project description:Background: Multiple autoantigens have been identified in membranous nephropathy (MN) by tissue-based proteomics. However, the antigenic targets of disease are unknown for >10% of MN and >50% of membranous lupus nephritis (MLN) cases. We identified multiple new targets in PLA2R-/THSD7A-/EXT-/NELL1-quadruple negative MN biopsies through mass spectrometry (MS) of immune complexes recovered from biopsy tissue of patients with MN. Methods: MN cases negative for PLA2R, THSD7A, EXT1/2, and NELL1 were identified from a biopsy database. Protein G immunoprecipitation was used to recover immune complexes from frozen biopsy tissue, followed by interrogation by mass spectrometry (MS). Potential antigens were confirmed through paraffin immunofluorescence of protein targets, followed by co-localization with IgG within immune deposits. Consecutive series of 165 cases of PLA2R-negative MN biopsies and 95 MLN biopsies was screened to determine the frequency for each potential antigen. Results: Seven protein targets were discovered within immune complexes from MN biopsies including FCN3, CD206, EEA1, SEZ6L2, NPR3, MST1, and VASN. Peptides from these proteins on MS were not enriched in PLA2R (n=86), THSD7A (n=64), NELL1 (n=64), or EXT1/2 (n=60) controls. Between 3-30 unique peptides were detected for each target. Frequencies of each antigen, determined by staining consecutive case series, were SEZ6L2 (1/165 idiopathic; 0/95 MLN), VASN (8/165 idiopathic; 2/95 MLN), EEA1 (6/165 idiopathic; 7/95 MLN), MST1 (6/165 idiopathic; 2/95 MLN), and FCN3 (0/165 idiopathic, 6/95 MLN), NPR3 and CD206 were positive in index cases. All cases showed co-localization of IgG within immune deposits. Conclusion: Seven novel protein targets were identified in MN and MLN.
2023-04-06 | PXD035854 | Pride
Project description:Plant homeodomain finger gene 6 (PHF6) encodes a 365-amino-acid protein containing two plant homology domain fingers. Germline mutations of human PHF6 cause Börjeson–Forssman–Lehmann syndrome, a congenital neurodevelopmental disorder. Loss-of-function mutations of PHF6 are detected in patients with acute leukemia, mainly of T cell lineage and in a small proportion of myeloid lineage. The functions of PHF6 in physiological hematopoiesis and leukemogenesis remain incompletely defined. To address this question, we generated a conditional Phf6 knockout mouse model and investigated the impact of Phf6 loss on the hematopoietic system. We found that Phf6 knockout mice at 8-week age had reduced numbers of CD4+ and CD8+ T cells in the peripheral blood compared to the wild-type littermates. There were decreased granulocyte-monocytic progenitors but increased Lin-c-Kit+Sca-1+ (LSK) cells in the marrow of young Phf6 knockout mice. Functional studies including competitive repopulation unit and serial transplantation assays revealed an enhanced reconstitution and self-renewal capacity in Phf6 knockout hematopoietic stem cells (HSCs). Aged Phf6 knockout mice had myelodysplasia-like presentations including decreased platelet counts, megakaryocyte dysplasia, and enlarged spleen related to extramedullary hematopoiesis. Moreover, we found that Phf6 loss lowered the threshold of NOTCH1-induced leukemic transformation at least partially through increased leukemia-initiating cells. Transcriptome analysis on the restrictive rare HSC subpopulations revealed upregulated cell cycling and oncogenic functions, with alteration of expression of key genes in those pathways. In summary, our studies demonstrate the in vivo crucial roles of Phf6 in physiological and malignant hematopoiesis.
2019-08-21 | GSE129465 | GEO