NKL homeobox gene activities in hematopoietic stem cells, T-cell development and T-cell leukemia

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) cells represent developmentally arrested T-cell progenitors, subsets of which aberrantly express homeobox genes of the NKL subclass, including TLX1, TLX3, NKX2-1, NKX2-5, NKX3-1 and MSX1. Here, we analyzed the transcriptional landscape of all 48 members of the NKL homeobox gene subclass in CD34+ hematopoietic stem and progenitor cells (HSPCs) and during lymphopoiesis, identifying activities of nine particular genes. Four of these were expressed in HSPCs (HHEX, HLX1, NKX2-3 and NKX3-1) and three in common lymphoid progenitors (HHEX, HLX1 and MSX1). Interestingly, our data indicated downregulation of NKL homeobox gene transcripts in late progenitors and mature T-cells, a phenomenon which might explain the oncogenic impact of this group of genes in T-ALL. Using MSX1-expressing T-ALL cell lines as models, we showed that HHEX activates while HLX1, NKX2-3 and NKX3-1 repress MSX1 transcription, demonstrating the mutual regulation and differential activities of these homeobox genes. Analysis of a public T-ALL expression profiling data set comprising 117 patient samples identified 20 aberrantly activated members of the NKL subclass, extending the number of known NKL homeobox oncogene candidates. While 7/20 genes were also active during hematopoiesis, the remaining 13 showed ectopic expression. Finally, comparative analyses of T-ALL patient and cell line profiling data of NKL-positive and NKL-negative samples indicated absence of shared target genes but instead highlighted deregulation of apoptosis as common oncogenic effect. Taken together, we present a comprehensive survey of NKL homeobox genes in early hematopoiesis, T-cell development and T-ALL, showing that these genes generate an NKL-code for the diverse stages of lymphoid development which might be fundamental for regular differentiation.

Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

“…To identify these absent factors, we sorted single iHECs from iRunx1-ESCs and performed single-cell RNA-Seq. In comparison with E11 T1-pre-HSCs (CD31 + CD41 low CD45 − ckit + CD201 high ), we identified eight hematopoietic-essential transcription factors, Hoxa5, 8 Hoxa7, 27 Hoxa9, 28 Hoxa10, 29 Hlf, 30 Ikzf1, 31 Nkx2-3, 32 and Setbp1, 33 which were barely expressed in iRunx1-ESC-derived iHECs but abundantly expressed in E11 T1-pre-HSCs ( Fig. 1b), consistent with the previous reports that human PSCderived HECs lack expression of HOXA family.…”

Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

“…To identify these absent factors, we sorted the single iHEC from iRunx1 -ESC and performed single-cell RNA-Seq. In comparison with E11 T1-pre-HSC (CD31 + CD41 low CD45 − c-kit + CD201 high ), we identified eight hematopoietic-essential transcription factors, Hoxa5 8 , Hoxa7 27 , Hoxa9 28 , Hoxa10 29 , Hlf 30 , Ikzf1 31 , Nkx2-3 32 , and Setbp1 33 , which were barely expressed in iRunx1 -ES-derived iHEC but abundantly expressed in E11 T1-pre-HSC (Fig. 1b).…”

Hippocampal lipidome and transcriptome profile alterations triggered by acute exposure of mice to GSM 1800 MHz mobile phone radiation: An exploratory study

“…The inhibition of RICTOR, which is part of the mTOR pathway, reveals the MP radiation impact on cell growth and survival and on oxidative phosphorylation and other mitochondrial functions (Li, Long, He, Belshaw, & Scott, 2015). The activation of NKX2-3 and MYCN, which are implicated in cell differentiation and oncogenesis (Kramer, Ribeiro, Arsenian-Henriksson, Deller, & Rohrer, 2016;Nagel et al, 2017), could be associated with previously reported brain protein expression alterations related to neurogenesis and brain plasticity demonstrated by Salford's group (Nittby, Grafstrom, et al, 2008) and our group , as well as with increased risk for brain tumor development (Hardell & Carlberg, 2009) following exposure to MP radiation. Finally, the activation of the last two regulators (IL-10 and EPO), which are cytokines related to microglia and implicated in inflammatory processes, neurodegenerative disorders, brain injuries, and antiapoptotic functions (Lobo-Silva, Carriche, , Roque, & Saraiva, 2016;Tamura et al, 2017), may be related to the robust EPA decrease that we found and to the cognitive dysfunction previously reported by our group following MP radiation exposure (Fragopoulou et al, 2010).…”