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.

Project description:Recently, we have reported a hematopoietic NKL-code which describes normal expression patterns of NKL homeobox genes in early hematopoiesis and lymphopoiesis including T-cell, B-cell and NK-cell development. This code allows the identification of deregulated NKL homeobox genes in lymphoid malignancies. Here, we report normal activities of NKL homeobox genes in myelopoiesis, thus, extending the NKL-code for the hematopoietic system. Analysis of public expression profiling data for developing and mature granulocytes, mast cells, monocytes, macrophages, megakaryocytes and erythrocytes revealed seven active myeloid NKL homeobox genes including DLX2, HHEX, HLX, HMX1, NANOG, NKX3-1 and VENTX. Furthermore, we analyzed public expression profiling data of 251 acute myeloid leukemia (AML) patients identifying 18 deregulated genes. These results indicated that NKL homeobox genes are frequently deregulated in this myeloid malignancy. For detailed analysis we focused on NKL homeobox gene NANOG which acts as stem cell factor and was accordingly expressed just in hematopoietic stem/progenitor cells. We detected aberrant NANOG expression in a small subset of AML patients and in AML cell line NOMO-1 which served as model to investigate upstream and downstream factors of this gene. Karyotyping and genomic profiling excluded rearrangements of the NANOG locus at 12p13. Analysis of NOMO-1 cells treated for NANOG knockdown, expression profiling analyses of HL-60 cells lentivirally transfected for NANOG overexpression, and of public AML patient data revealed regulators and target genes of NANOG. NKL homeobox genes HHEX and MSX1 and the NOTCH-pathway were located upstream of NANOG and HHEX, HLX, VENTX, MYB, CDK6, MAML2 and MIR17HG represented target genes of NANOG in the myeloid context. In conclusion, we described a myeloid NKL-code and several deregulated NKL homeobox genes in AML. We identified for NKL homeobox gene NANOG deregulating factors and downstream activities in AML. These data indicate a common oncogenic role of NKL homeobox genes in myeloid malignancies.

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.

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Deregulated expression of NKL homeobox genes in T-cell lymphomas

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