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Expression data from AZA treated megakaryocytic cells under TPO-RA stimulation

ABSTRACT: Thrombocytopenia is an independent prognostic indicator in patients with MDS (de Swart, L. et al, Br J Haematol, 2015) and we sought to evaluate the contribution of azacitidine to the worsening of this condition in patients with MDS and acute myeloid leukemia (AML). Since MDS/AML may have lower amounts of residual healthy cells, we sought to model this effect of AZA on healthy cord blood derived megakaryocytic cells. We used microarrays to detail the global programme of gene expression in the presence of azacitidine under megakaryocytic differentiation stimulants and identified distinct classes of dysregulated genes and pathways during this process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144410 | GEO | 2022/08/25

REPOSITORIES: GEO

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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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Expression data from AZA treated megakaryocytic cells under TPO-RA stimulation

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