Hhex induces promyelocyte self-renewal and cooperates with growth factor independence to cause myeloid leukemia in mice

Jackson, Jacob T.; Ng, Ashley P; Shields, Benjamin; Haupt, Sue; Haupt, Ygal; McCormack, Matthew P.

doi:10.1182/bloodadvances.2017013243

Cited by 10 publications

(10 citation statements)

References 44 publications

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“…Using in situ hybridization, we indeed observed that endothelial hhex expression was increased in hhex mutants. This finding is consistent with a recent report in hematopoietic cells 39 .…”

Section: Discussionsupporting

confidence: 94%

HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development

et al. 2018

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Formation of the lymphatic system requires the coordinated expression of several key regulators: vascular endothelial growth factor C (VEGFC), its receptor FLT4, and a key transcriptional effector, PROX1. Yet, how expression of these signaling components is regulated remains poorly understood. Here, using a combination of genetic and molecular approaches, we identify the transcription factor hematopoietically expressed homeobox (HHEX) as an upstream regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation in vertebrates. By analyzing zebrafish mutants, we found that hhex is necessary for sprouting angiogenesis from the posterior cardinal vein, a process required for lymphangiogenesis. Furthermore, studies of mammalian HHEX using tissue-specific genetic deletions in mouse and knockdowns in cultured human endothelial cells reveal its highly conserved function during vascular and lymphatic development. Our findings that HHEX is essential for the regulation of the VEGFC/FLT4/PROX1 axis provide insights into the molecular regulation of lymphangiogenesis.

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“…Using in situ hybridization, we indeed observed that endothelial hhex expression was increased in hhex mutants. This finding is consistent with a recent report in hematopoietic cells 39 .…”

Section: Discussionsupporting

confidence: 94%

HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development

et al. 2018

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“…As reported so far, aberrantly expressed NKL homeobox genes in AML include DLX1 and DLX2 [18], HHEX [54,55], HLX [19], MSX1 [56], NANOG [57], and VENTX [20,58]. Our study added several other NKL subclass members to this list.…”

Section: Discussionmentioning

confidence: 81%

NKL homeobox gene activities in normal and malignant myeloid cells

Nagel¹,

Scherr²,

MacLeod³

et al. 2019

PLoS ONE

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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.

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“…In addition, TGF β signaling downregulates HHEX activity and induces an EMT that facilitates cell migration (Marcolino et al, 2020 ). HHEX induces promyelocyte self-renewal and cooperates with growth factor independence to cause myeloid leukemia in mice (Jackson et al, 2018 ). HHEX regulates the self-renewal of hematopoietic stem cell (HSC), emergency hematopoiesis, and the initiation of acute myeloid leukemia (AML) via repression of the Cdkn2a tumor suppressor locus (Jackson et al, 2017 , 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological Significances of Cancer Stem Cell-Associated HHEX Expression in Breast Cancer

Zhang

Zhao

et al. 2020

Front. Cell Dev. Biol.

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Aberrant expression of the transcription factor hematopoietic ally expressed homeobox/proline-rich homeodomain (HHEX/PRH) is implicated in numerous cancers. However, the association of HHEX with breast cancer (BC) remains unclear. In this study, HHEX mRNA and protein expression were analyzed using the Oncomine, UALCAN, GEPIA, TCGAportal, and HPA databases. We evaluated the effect of HHEX on clinicopathological parameters using Kaplan–Meier plotter, OncoLnc, TCGAportal, PROGgeneV2, and BC-GenExMiner. Western blotting was performed to compare the level of HHEX in breast samples of Tientsin Albino 2 mice, human breast precancerous lesions, benign breast tumors, and BC. The correlation between HHEX and cancer stem cells was investigated using the GEO (GSE52327 and GSE94865) and GEPIA datasets. Networks between HHEX and survival-related gene marker sets and microRNAs were analyzed using GEPIA, StarBase, and Cytoscape. Results of this study showed that HHEX expression in BC was significantly lower than those in breast precancerous lesions and benign breast tumors at both mRNA and protein levels. BC patients with lower HHEX expression had significantly worse overall survival and disease-free survival. Moreover, HHEX significantly affected the clinicopathology of BC. Specifically, low HHEX expression was correlated with the following groups of patients: age ≤51 years, ER-negative or PR-negative patients, HER-2 positive, triple-negative breast cancer, and basal-like BC. Immunohistochemical analysis of the breast samples showed significant differences of HHEX staining index (P < 0.001) among the three groups. To further investigate the mechanism, we determined the intersection of differentially expressed genes related to BC stem cells and those genes after HHEX expression was altered. This led to the identification of four potentially regulated genes-CXL12, BLNK, PAG1, and LPXN. Using StarBase and km-plotter, the negative regulation of HHEX expression and survival trends, including miR-130b, miR-30e, and miR-301b were joined into miRNA-HHEX-mRNA potential regulatory network. The abilities of proliferation, migration and invasion increased in MDA-MB-231 and BT-549 breast cancer cell lines after HHEX down expression and decreased after HHEX overexpression compared them in the control cells. In conclusion, these data suggest that HHEX expression is downregulated in BC and HHEX may regulate the development of BC through the stem cell-related genes.

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Hhex induces promyelocyte self-renewal and cooperates with growth factor independence to cause myeloid leukemia in mice

Abstract: Key Points• Overexpression of Hhex transcription factor blocks myeloid differentiation at the promyelocyte stage.• Hhex cooperates with growth factor independence to elicit rapid promyelocytic leukemia in mice.

Cited by 10 publications

References 44 publications

HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development

HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development

NKL homeobox gene activities in normal and malignant myeloid cells

Clinicopathological Significances of Cancer Stem Cell-Associated HHEX Expression in Breast Cancer

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