Aberrant expression of NKL homeobox genes HMX2 and HMX3 interferes with cell differentiation in acute myeloid leukemia
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq 6000
ORGANISM(S): Homo sapiens
SUBMITTER: Claudia Pommerenke
PROVIDER: E-MTAB-9079 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Homeobox genes encode transcription factors regulating basic processes in cell differentiation during embryogenesis and in the adult. Recently, we have reported the NKL-code which describes physiological expression patterns of nine NKL homeobox genes in early hematopoiesis and in lymphopoiesis including main stages of T-, B- and NK-cell development. Aberrant activity of NKL homeobox genes is involved in the generation of hematological malignancies including T-cell leukemia. Here, we searched for deregulated NKL homeobox genes in main entities of T-cell lymphomas comprising peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), hepatospleenic T-cell lymphoma (HSTL), and NK/T-cell lymphoma (NKTL). Our data revealed in all types altogether 19 aberrantly overexpressed genes, demonstrating that deregulated NKL homeobox genes play a significant role in T-cell lymphomas as well. For detailed analyses we focused on NKL homeobox gene MSX1 which is normally expressed in NK-cells and aberrantly activated in T-cell leukemia. This gene was overexpressed in subsets of HSTL patients and HSTL-derived sister cell lines DERL-2 and DERL-7 which served as models to identify mechanisms of deregulation. We performed genomic and expression profiling and whole genome sequencing and revealed mutated and deregulated gene candidates including the fusion gene CD53-PDGFRB exclusively expressed in DERL-2. Subsequent knockdown experiments allowed the construction of an aberrant network involved in MSX1 deregulation containing chromatin factors AUTS2 and H3B/H3.1, PDGF- and BMP-signalling pathways, and homeobox genes NKX2-2 and PITX1. The gene encoding AUTS2 is located at 7q11 and may represent a basic target of the HSTL hallmark aberration i(7q). Our data indicate both oncogenic and tumor suppressor functions of MSX1 in HSTL, reflecting its activity in early lineage differentiation of T- and NK-cells and the presence of NK-cell like characteristics in malignant HSTL cells. In this context, NKL homeobox gene MSX1 may represent a selective target in HSTL tumor evolution. Together, the data highlight an oncogenic role of deregulated NKL homeobox genes in T-cell lymphoma and identified MSX1 as a novel player in HSTL, involved in aberrant NK- and T-cell differentiation.
2019-11-01 | E-MTAB-7734 | biostudies-arrayexpress
Project description:Patients suffering from chronic lymphocytic leukemia (CLL) display highly diverse clinical courses ranging from indolent cases to aggressive disease with genetic and epigenetic features resembling this diversity. Here, we developed a comprehensive approach combining a variety of molecular and clinical data to identify translocation events disrupting long-range chromatin interactions and causing cancer-relevant transcriptional deregulation. Thereby, we identified a B cell specific cis-regulatory element restricting the expression of genes in the associated locus, including PRMT5 and DAD1, two factors with oncogenic potential. Examining the role of PRMT5 in CLL identified transcriptional programs associated with pathways of stress tolerance and growth support, maintaining MYC-driven gene expression in vivo and in vitro. Conversely, inhibition of PRMT5 impairs factors involved in DNA-repair and sensitizes cells for apoptosis. Finally, we show that artificial deletion of the regulatory element from its endogenous context resulted in upregulation of corresponding genes, including PRMT5. Furthermore, such disruption renders PRMT5 transcription vulnerable to additional stimuli and subsequently also alters the expression of downstream PRMT5 targets.
2020-08-19 | E-MTAB-8203 | biostudies-arrayexpress
Project description:Retaining the mutational pattern of tumors, immortalized cell lines represent excellent tools for the molecular study of genetic aberrations. Tumors can consist of subclones which develop under selective forces driven by mutational alterations. This explains why after therapy, relapsed clones can be genetically distinct from clones at diagnosis. We analyzed the mutational patterns of pairs of cell lines raised at early and late phases of development from patients with a hematopoietic tumor named pre-B acute lymphoblastic leukemia (ALL). All cell lines tested showed mutations that typically occur in this tumor. We also observed clonal differences in sister cell lines, genetic aberrations developing during disease progression. Especially noteworthy was the presence of two mutations which are hitherto undescribed in cell lines.
2021-12-02 | E-MTAB-11039 | biostudies-arrayexpress
Project description:For many years, immortalized cell lines have been used as model systems for cancer research. Cell line panels were established for basic research and drug development, but did not cover the full spectrum of leukemia and lymphoma. Therefore, we now developed a novel panel (LL-100), 100 cell lines covering 22 entities of human leukemia and lymphoma including T-cell, B-cell and myeloid malignancies. Importantly, all cell lines are unequivocally authenticated and assigned to the correct tissue. Cell line samples were proven to be free of mycoplasma and virus contamination. Whole exome sequencing (WES) and RNA sequencing (RNA-seq) of the hundred authenticated leukemia-lymphoma cell lines were conducted with a uniform methodology to complement existing data on these publicly available cell lines. This part captures WES. This data set will be useful for understanding the function of oncogenes and tumor suppressor genes and to develop targeted therapies.
2019-05-28 | E-MTAB-7722 | biostudies-arrayexpress
Project description:Retaining the mutational pattern of tumors, immortalized cell lines represent excellent tools for the molecular study of genetic aberrations. Tumors can consist of subclones which develop under selective forces driven by mutational alterations. This explains why after therapy, relapsed clones can be genetically distinct from clones at diagnosis. We analyzed the mutational patterns of pairs of cell lines raised at early and late phases of development from patients with a hematopoietic tumor named pre-B acute lymphoblastic leukemia (ALL). All cell lines tested showed mutations that typically occur in this tumor. We also observed clonal differences in sister cell lines, genetic aberrations developing during disease progression. Especially noteworthy was the presence of two mutations which are hitherto undescribed in cell lines.
2021-12-02 | E-MTAB-11038 | biostudies-arrayexpress
Project description:For many years, immortalized cell lines have been used as model systems for cancer research. Cell line panels were established for basic research and drug development, but did not cover the full spectrum of leukemia and lymphoma. Therefore, we now developed a novel panel (LL-100), 100 cell lines covering 22 entities of human leukemia and lymphoma including T-cell, B-cell and myeloid malignancies. Importantly, all cell lines are unequivocally authenticated and assigned to the correct tissue. Cell line samples were proven to be free of mycoplasma and virus contamination. Whole exome sequencing (WES) and RNA sequencing (RNA-seq) of the hundred authenticated leukemia-lymphoma cell lines were conducted with a uniform methodology to complement existing data on these publicly available cell lines. This part captures RNA-Seq. This data set will be useful for understanding the function of oncogenes and tumor suppressor genes and to develop targeted therapies.
2019-05-28 | E-MTAB-7721 | biostudies-arrayexpress
Project description:Patients suffering from chronic lymphocytic leukemia (CLL) display highly diverse clinical courses ranging from indolent cases to aggressive disease with genetic and epigenetic features resembling this diversity. Here, we developed a comprehensive approach combining a variety of molecular and clinical data to identify translocation events disrupting long-range chromatin interactions and causing cancer-relevant transcriptional deregulation. Thereby, we identified a B cell specific cis-regulatory element restricting the expression of genes in the associated locus, including PRMT5 and DAD1, two factors with oncogenic potential. Examining the role of PRMT5 in CLL identified transcriptional programs associated with pathways of stress tolerance and growth support, maintaining MYC-driven gene expression in vivo and in vitro. Conversely, inhibition of PRMT5 impairs factors involved in DNA-repair and sensitizes cells for apoptosis. Finally, we show that artificial deletion of the regulatory element from its endogenous context resulted in upregulation of corresponding genes, including PRMT5. Furthermore, such disruption renders PRMT5 transcription vulnerable to additional stimuli and subsequently also alters the expression of downstream PRMT5 targets.
2020-08-19 | E-MTAB-8219 | biostudies-arrayexpress
Project description:RNA-seq of NOMO-1 cell line
2019-08-30 | E-MTAB-8010 | biostudies-arrayexpress
Project description:NKL homeobox genes encode transcription factors which impact normal development and hematopoietic malignancies if deregulated. Recently, we established a NKL-code which describes the physiological expression pattern of eleven NKL homeobox genes in the course of hematopoiesis, allowing evaluation of aberrantly activated NKL-genes in leukemia/lymphoma. Here, we identify ectopic expression of NKL homeobox gene NKX2-4 in erythroblastic acute myeloid leukemia (AML) cell line OCI-M2 and describe investigation of its activating factors and target genes. Comparative expression profiling data of AML cell lines revealed in OCI-M2 an aberrantly activated program for endothelial development including master factor ETV2 and the additional endothelial signature genes HEY1, IRF6 and SOX7. SiRNA-mediated knockdown experiments showed their role in activating NKX2-4 expression. Furthermore, the ETV2 locus at 19p13 was genomically amplified, possibly underlying its aberrant expression. Target gene analyses of NKX2-4 revealed activated ETV2, HEY1 and SIX5, and suppressed FLI1. Comparative expression profiling analysis of public datasets for AML patients and primary megakaryocyte-erythroid progenitor cells showed conspicuous similarities to NKX2-4 activating factors and target genes we identified, supporting the clinical relevance of our findings and developmental disturbance by NKX2-4. Finally, identification and target gene analysis of aberrantly expressed NKX2-3 in AML patients and megakaryoblastic AML cell line ELF-153 showed activation of FLI1, contrasting with OCI-M2. FLI1 encodes a master factor for myelopoiesis, driving megakaryocytic and suppressing erythroid differentiation, thus representing a basic developmental target of these homeo-oncogenes. Taken together, we have identified aberrantly activated NKL homeobox genes NKX2-3 and NKX2-4 in AML, deregulating megakaryocytic and erythroid differentiation processes, and thereby driving formation specific AML subtypes.
2021-10-31 | E-MTAB-10941 | biostudies-arrayexpress
Project description:Recently, we have documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in human myelopoiesis including monocytes and their derived dendritic cells (DCs). Here, we enlarge this map to include normal NKL homeobox gene expressions in progenitor-derived DCs. Analysis of public gene expression profiling and RNA-seq datasets containing plasmacytoid and conventional dendritic cells (pDC and cDC) demonstrated HHEX activity in both entities while cDCs expressed additionally VENTX. The subsequent aim of our study was to examine regulation and function of VENTX in DCs. We compared profiling data of VENTX-positive cDC and monocytes with VENTX-negative pDC and common myeloid progenitor entities and revealed several differentially expressed genes encoding transcription factors and pathway components, representing potential VENTX regulators. Screening of RNA-seq data for 100 leukemia/lymphoma cell lines identified prominent VENTX expression in acute myelomonocytic leukemia cell line MUTZ-3 containing inv(3)(q21q26) and t(12;22)(p13;q11) and representing a model for DC differentiation studies. Furthermore, extended gene analyses indicated that MUTZ-3 is associated with the subtype cDC2. Subsequent knockdown experiments and modulations of signalling pathways in MUTZ-3 and control cell lines, in addition to analysis of public chromatin immune-precipitation data confirmed identified candidate transcription factors CEBPB, ETV6, EVI1, GATA2, IRF2, MN1, SPIB and SPI1 and the CSF-, NOTCH- and TNFa-pathways as VENTX regulators. Live-cell imaging analyses of MUTZ-3 cells treated for VENTX knockdown excluded impacts in apoptosis or induced alteration of differentiation-associated cell morphology. In contrast, target gene analysis performed by expression profiling of knockdown-treated MUTZ-3 cells revealed VENTX-mediated activation of several cDC-specific genes including CSFR1, EGR2 and MIR10A and inhibition of pDC-specific genes like RUNX2. Taken together, we added NKL homeobox gene activities for progenitor-derived DCs to the NKL-code, showing that VENTX is expressed in cDCs but not in pDCs and part of a cDC-specific gene regulatory network operating in DC differentiation and function.
2021-12-01 | E-MTAB-10277 | biostudies-arrayexpress