Dataset Information

Aberrant activity of NKL homeobox gene NKX3-2 in a T-ALL subset.

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy originating from T-cell progenitors in which differentiation is blocked at early stages. Physiological expression of specific NKL homeobox genes obeys a hematopoietic NKL-code implicated in the process of lymphopoiesis while in differentiated T-cells these genes are silenced. We propose that this developmental expression pattern underlies the observation that NKL homeobox genes are the most ubiquitous group of transcription factors deregulated in T-ALL, including TLX1, TLX3, NKX2-5 and NKX3-1. Here, we describe a novel member of the NKL homeobox gene subclass, NKX3-2 (BAPX1), which is aberrantly activated in 18% of pediatric T-ALL patients analyzed while being normally expressed in developing spleen. Identification of NKX3-2 expression in T-ALL cell line CCRF-CEM qualified these cells to model its deregulation and function in a leukemic context. Genomic and chromosomal analyses demonstrated normal configuration of the NKX3-2 locus at chromosome 4p15, thus excluding cytogenetic dysregulation. Comparative expression profiling analysis of NKX3-2 patient data revealed deregulated activity of BMP- and MAPK-signalling. These candidate pathways were experimentally confirmed to mediate aberrant NKX3-2 expression. We also show that homeobox gene SIX6, plus MIR17HG and GATA3 are downstream targets of NKX3-2 and plausibly contribute to the pathogenesis of this malignancy by suppressing T-cell differentiation. Finally, NKL homeobox gene NKX2-5 was activated by NKX3-2 in CCRF-CEM and by FOXG1 in PEER, representing mutually inhibitory activators of this translocated oncogene. Together, our findings reveal a novel oncogenic NKL homeobox gene subclass member which is aberrantly expressed in a large subset of T-ALL patients and participates in a deregulated gene network likely to arise in developing spleen.

SUBMITTER: Nagel S

PROVIDER: S-EPMC5944955 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Aberrant activity of NKL homeobox gene NKX3-2 in a T-ALL subset.

Nagel Stefan S Meyer Corinna C Kaufmann Maren M Zaborski Margarete M MacLeod Roderick A F RAF Drexler Hans G HG

PloS one 20180510 5

T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy originating from T-cell progenitors in which differentiation is blocked at early stages. Physiological expression of specific NKL homeobox genes obeys a hematopoietic NKL-code implicated in the process of lymphopoiesis while in differentiated T-cells these genes are silenced. We propose that this developmental expression pattern underlies the observation that NKL homeobox genes are the most ubiquitous group of transcriptio ...[more]

PMID: 29746601

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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.

Project description:Recently, we have documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in early hematopoiesis and in lymphopoiesis, which spotlights genes deregulated in lymphoid malignancies. Here, we enlarge this map to include normal NKL homeobox gene expressions in myelopoiesis by analyzing public expression profiling data and primary samples from developing and mature myeloid cells. We thus uncovered differential activities of six NKL homeobox genes, namely DLX2, HHEX, HLX, HMX1, NKX3-1 and VENTX. We further examined public expression profiling data of 251 acute myeloid leukemia (AML) and 183 myelodysplastic syndrome (MDS) patients, thereby identifying 24 deregulated genes. These results revealed frequent deregulation of NKL homeobox genes in myeloid malignancies. For detailed analysis we focused on NKL homeobox gene NANOG, which acts as a stem cell factor and is correspondingly expressed alone in hematopoietic progenitor cells. We detected aberrant expression of NANOG in a small subset of AML patients and in AML cell line NOMO-1, which served as a model. Karyotyping and genomic profiling discounted rearrangements of the NANOG locus at 12p13. But gene expression analyses of AML patients and AML cell lines after knockdown and overexpression of NANOG revealed regulators and target genes. Accordingly, NKL homeobox genes HHEX, DLX5 and DLX6, stem cell factors STAT3 and TET2, and the NOTCH-pathway were located upstream of NANOG while NKL homeobox genes HLX and VENTX, transcription factors KLF4 and MYB, and anti-apoptosis-factor MIR17HG represented target genes. In conclusion, we have extended the NKL-code to the myeloid lineage and thus identified several NKL homeobox genes deregulated in AML and MDS. These data indicate a common oncogenic role of NKL homeobox genes in both lymphoid and myeloid malignancies. For misexpressed NANOG we identified an aberrant regulatory network, which contributes to the understanding of the oncogenic activity of NKL homeobox genes.

Project description:The NKL-code describes normal expression patterns of NKL homeobox genes in hematopoiesis. Aberrant expression of NKL homeobox gene subclass members have been reported in several hematopoietic malignancies including acute myeloid leukemia (AML). Here, we analyzed the oncogenic role of the HMX-group of NKL homeobox genes in AML. Public expression profiling data-available for HMX1 and HMX2-indicate aberrant activity of HMX2 in circa 2% AML patients overall, rising to 31% in those with KMT2A/MLL rearrangements whereas HMX1 expression remains inconspicuous. AML cell lines EOL-1, MV4-11 and MOLM-13 expressed both, HMX2 and neighboring HMX3 genes, and harbored KMT2A aberrations, suggesting their potential functional association. Surprisingly, knockdown experiments in these cell lines demonstrated that KMT2A inhibited HMX2/3 which, in turn, did not regulate KMT2A expression. Furthermore, karyotyping and genomic profiling analysis excluded rearrangements of the HMX2/3 locus in these cell lines. However, comparative expression profiling and subsequent functional analyses revealed that IRF8, IL7- and WNT-signalling activated HMX2/3 expression while TNFa/NFkB- signalling proved inhibitory. Whole genome sequencing of EOL-1 identified two mutations in the regulatory upstream regions of HMX2/3 resulting in generation of a consensus ETS-site and transformation of a former NFkB-site into an SP1-site. Reporter-gene assays demonstrated that both mutations contributed to HMX2/3 activation, modifying ETS1/ELK1- and TNFalpha-mediated gene regulation. Moreover, DMSO-induced eosinophilic differentiation of EOL-1 cells coincided with HMX2/3 downregulation while knockdown of HMX2 induced cell differentiation, collectively supporting a fundamental role for these genes in myeloid differentiation arrest. Finally, target genes of HMX2/3 were identified in EOL-1 and included suppression of differentiation gene EPX, and activation of fusion gene FIP1L1-PDGFRA and receptor-encoding gene HTR7, both of which enhanced oncogenic ERK-signalling. Taken together, our study documents a leukemic role for deregulated NKL homeobox genes HMX2 and HMX3 in AML, revealing molecular mechanisms of myeloid differentiation arrest.

Dataset Information

Aberrant activity of NKL homeobox gene NKX3-2 in a T-ALL subset.

Publications

Aberrant activity of NKL homeobox gene NKX3-2 in a T-ALL subset.

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