The NKL-code for innate lymphoid cells reveals deregulated expression of NKL homeobox genes HHEX and HLX in anaplastic large cell lymphoma (ALCL)

Nagel, Stefan; Pommerenke, Claudia; MacLeod, Roderick A.F.; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans

doi:10.18632/oncotarget.27683

Cited by 13 publications

(26 citation statements)

References 103 publications

(150 reference statements)

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“…In several studies, we examined the physiological expression pattern of NKL homeobox genes in stem cells, progenitors and terminally differentiated blood cells across the whole hematopoietic spectrum. The lymphoid lineage was analyzed in four studies using public datasets of developing and mature T-cells, B-cells, NK-cells and ILCs [ 26 , 27 , 28 , 29 ]. Datasets covering the myeloid lineage were analyzed in a single study [ 30 ].…”

Section: Nkl-code In Hematopoiesismentioning

confidence: 99%

“…Altogether, eleven NKL homeobox genes were identified, comprising DLX2, HHEX, HLX, HMX1, MSX1, NANOG, NKX2-3, NKX3-1, NKX6-3, TLX2 and VENTX. Their unique expression pattern has been termed NKL-code [ 26 , 27 , 28 , 29 , 30 ].…”

Section: Nkl-code In Hematopoiesismentioning

confidence: 99%

“…HLX: H2.0-like homeobox (HLX) is overexpressed in several hematopoietic malignancies including HL, DLBCL and anaplastic large cell lymphoma (ALCL) [ 27 , 29 ]. Aberrant activation by STAT3 plays a dominant role in HLX expression in these tumor types.…”

Section: Deregulated Nkl Homeobox Genes In Hematopoietic Malignanciesmentioning

confidence: 99%

“…Finally, STAT3 represents a hallmark factor in ALCL [ 93 ]. Analyses of several ALCL cell lines revealed genomic gains at STAT3 and HLX loci and demonstrated a direct activating impact of STAT3 in HLX expression, highlighting HLX as important oncogene and STAT3-target in this malignancy [ 29 ].…”

Section: Deregulated Nkl Homeobox Genes In Hematopoietic Malignanciesmentioning

confidence: 99%

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NKL-Code in Normal and Aberrant Hematopoiesis

Nagel

2021

Cancers

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We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the developmental impact of NKL homeobox genes, these data suggest a key role for their activity in normal hematopoietic differentiation processes. On the other hand, the aberrant overexpression of NKL-code-members or the ectopical activation of non-code members have been frequently reported in lymphoid and myeloid leukemia/lymphoma, revealing the oncogenic potential of these genes in the hematopoietic compartment. Here, I provide an overview of the NKL-code in normal hematopoiesis and instance mechanisms of deregulation and oncogenic functions of selected NKL genes in hematologic cancers. As well as published clinical studies, our conclusions are based on experimental work using hematopoietic cell lines which represent useful models to characterize the role of NKL homeobox genes in specific tumor types.

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Section: Nkl-code In Hematopoiesismentioning

confidence: 99%

Section: Nkl-code In Hematopoiesismentioning

confidence: 99%

Section: Deregulated Nkl Homeobox Genes In Hematopoietic Malignanciesmentioning

confidence: 99%

Section: Deregulated Nkl Homeobox Genes In Hematopoietic Malignanciesmentioning

confidence: 99%

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NKL-Code in Normal and Aberrant Hematopoiesis

Nagel

2021

Cancers

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“…STAT3 operates as major activator of HLX expression. This impact plays an oncogenic role in anaplastic large cell lymphoma where STAT3 represents a hallmark factor [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

NKL Homeobox Gene VENTX Is Part of a Regulatory Network in Human Conventional Dendritic Cells

Nagel

Pommerenke

Meyer

et al. 2021

IJMS

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Recently, we 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 additionally expressed VENTX. The consequent 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 an 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. In addition to analysis of public chromatin immune-precipitation data, subsequent knockdown experiments and modulations of signaling pathways in MUTZ-3 and control cell lines 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 on 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 forms part of a cDC-specific gene regulatory network operating in DC differentiation and function.

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