Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Epigenetically Induced Ectopic Expression of UNCX in Acute Myeloid Leukemia Associated with Impaired Proliferation and Differentiation of Myeloid Cells

ABSTRACT: We performed gene-expression profiling (GEP) of UNCX-positive versus UNCX-negative AML patients using exon-array and gene-pathway analyses. UNCX is a homeobox gene ectopically expressed in acute myeloid leukemia (AML) patients and cell lines, whose activation is induced by epigenetic modifications. Our results showed a novel leukemogenic role of UNCX in slowing myeloid cell proliferation with a differentiation arrest in AML blasts. Accordingly, UNCX expression characterizes AML cells at early stage of differentiation, mainly M2 and M3 FAB types carrying wild-type NPM1. Overall, our findings provide new relevant insights into the role of epigenetically activated homeobox genes in leukemogenesis, defining a new subgroup of AML patients.

ORGANISM(S): Homo sapiens

SUBMITTER: Orazio Palumbo

PROVIDER: E-MTAB-4098 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Epigenetically Induced Ectopic Expression of UNCX in Acute Myeloid Leukemia Associated with Impaired Proliferation and Differentiation of Myeloid Cells

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