TLX1/HOX11 transcription factor inhibits differentiation and promotes a non‐haemopoietic phenotype in murine bone marrow cells

Abstract

Summary The TLX/HOX11 subfamily of divergent homeobox genes are involved in various aspects of embryogenesis and, in the case of TLX1/HOX11 and TLX3/HOX11L2, feature prominently as oncogenes in human T‐cell acute lymphoblastic leukaemia. TLX1 possesses immortalising activity in a wide variety of blood cell lineages, however, the effect of this oncogene on haemopoietic cell differentiation has not been fully investigated. We therefore constitutively expressed TLX1 in murine bone marrow or fetal liver cells using retroviral transfer followed by transplantation and/or in vitro culture. TLX1 was found to dramatically alter haemopoiesis, promoting the emergence of a non‐haemopoietic CD45− CD31+ cell population while markedly inhibiting erythroid and granulocytic cell differentiation. To identify genetic programs perturbed by TLX1, a comparison of transcript profiles from J2E erythroid cells with and without enforced TLX1 expression was undertaken. This revealed a pattern of gene expression indicative of enhanced proliferation coupled to differentiation arrest. Of the genes identified, two, KIT and VEGFC, were found to be potential TLX1 targets based on transcriptional assays. These results demonstrate that TLX1 can act broadly to impair haemopoiesis and divert differentiation to an alternative fate. This may account for its ability to promote the pre‐leukaemic state via perturbation of specific gene expression programs.

The DN2 Myeloid-T (DN2mt) Progenitor is a Target Cell for Leukemic Transformation by the TLX1 Oncogene

“…These included Ccna2, Ccnb1, Ccnb2, Cdc20 [14,16], Cdc25a [26], Cdc6, Mcm2, Mcm4, Mcm5, Mcm6, Rad51, Top2a and Ttk [24]. To this set, we added TLX1 ChIP-chip targets that were shown to be directly activated by CUX1 and relevant to the establishment of bipolar mitoses leading to CIN (Aurkb, Bub1, Bub3, Camk2d, Cenpa, Cenpe, Kifc1, Kif2c, Mad2l1, Nek2, Ttk and Zw10) [73].…”

NKL homeobox genes in leukemia

“…On the other hand, these genes might mimic NKL genes that have a role in normal T-cell development, thereby making use of existing pathways, in line with a 'lineage-survival model'. HHEX 49 and MSX2 67 have both been proposed as candidate genes that might be mimicked by ectopically expressed NKL genes. HHEX is highly expressed in early hematopoietic progenitors and downregulated upon T-cell differentiation.…”

“…In general, NKL genes function predominantly as transcriptional repressors, although activating properties have also been described. 49,102,103 More than half (32/48) of the NKL homeodomain proteins contain a conserved Engrailed homology 1 (Eh1) motif (FxIxxIL, whereby x can be any amino acid) 104,105 at their N terminal (defined here as having at least 3 out of 4 conserved amino acids present at the correct position at the N-terminal side, Table 1). The Eh1 domain functions as a strong transcriptional repressor.…”

Knockdown of Fanconi anemia genes in human embryonic stem cells reveals early developmental defects in the hematopoietic lineage

“…Comparisons of differentially expressed HOX genes revealed Caudal type homeobox 1 (CDX1), T-cell leukemia homeobox 1 (TLX1), and HOXD3 among the most significantly decreased in both FANCAi and FANCD2i day 20 EBs (Figure 6G). CDX1 and TLX1 have known roles in hematopoietic specification and progenitor proliferation, 43,44 whereas HOXD3 has been shown to play a role in patterning the anterior-posterior axis and the embryonic skeleton. 45 In addition to their role in tissue specification, HOX genes have been shown to directly influence the cell cycle machinery and cellular proliferation.…”