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.
Highlights
The source of the human blood system is located in the bone marrow where hematopoietic stem and progenitor cells (HSPC) generate progenitors of both the myeloid and lymphoid lineages
Expression profiling data obtained from primary HSPCs and selected T-cell acute lymphoblastic leukemia (T-ALL) cell lines were illustrated as a heatmap in Fig 1A, showing transcript levels of 37 NKL homeobox genes
These data indicated that three genes, namely HHEX, HLX1 and NKX2-3, were physiologically expressed in HSPCs, while the analyzed T-ALL cell lines aberrantly expressed HHEX, MSX1, NKX2-5, NKX31, TLX1 and TLX3 as reported previously [8,10,15,16,31]
Summary
The source of the human blood system is located in the bone marrow where hematopoietic stem and progenitor cells (HSPC) generate progenitors of both the myeloid and lymphoid lineages. The common lymphoid progenitors (CLP) differentiate into T-cells, B-cells or NK-cells. The subsequent T-cell development begins with the early T-cell progenitors (ETP) which migrate into the thymus where their terminal differentiation proceeds toward mature CD4+ and CD8+ T-cells. Major T-cell signalling pathways include NOTCH, T-cell receptor (TCR), and MAPK. These pathways govern differentiation and selection processes which are important for the generation of functional non-autoimmune T-cells, triggering apoptosis in disqualified cells [1,2]. Bone morphogenic protein (BMP) signalling represents an additional pathway which regulates the development of early T-cells [3,4]. Transcriptional regulation plays a prominent role for T-cell development [5]
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