Transcriptional activation of the cardiac homeobox gene CSX1/NKX2-5 in a B-cell chronic lymphoproliferative disorder

Abstract

Homeobox containing transcription factors are frequently deregulated in human hematologic malignant diseases either indirectly through an abnormality of an upstream factor, or directly through rearrangement of the gene itself. Study of T-cell acute lymphoblastic leukemia identified the related non-clustered homeobox transcription factors, TLX1 and TLX3, as frequently ectopically expressed as a result of chromosomal translocations. We report the deregulation of a non-clustered homeobox gene in a new type of t(5;14)(q35;q11) translocation in a mature peripheral B-cell leukemia. This translocation results in the ectopic expression of the CSX1/NKX2-5 gene on chromosome 5q35 due to its juxtaposition to the TCR δ gene on chromosome 14q11. Expression of the CSX1/NKX2-5 protein conferred enhanced replating potential to transduced murine bone marrow cells. Our study establishes that deregulation of homeobox encoding genes is not restricted to acute leukemic proliferations, but is also observed in chronic malignant diseases.

Haemogenic endocardium contributes to transient definitive haematopoiesis

“…However, the identification of Nkx2-5-positive/derived endocardium and yolk sac endothelium raises the possibility that Nkx2-5 is directly involved in embryonic hematopoiesis. Indeed, ectopic expression of NKX2-5 is found in the leukemic cells in children with T- and B-cell acute lymphoblastic leukemia with t(5;14) translocation 36 , 37 . Given that the molecular pathways regulating on cogenesis often recapitulate aberrations of processes governing embryogenesis, these clinical observations support the idea that Nkx2-5 plays a direct role during hematopoiesis.…”

Nkx2.5 marks angioblasts that contribute to hemogenic endothelium of the endocardium and dorsal aorta

“…Nkx2-5 and Isl1 are expressed in and required for a distinct subset of endocardial cells defined as the hemogenic endocardium, proposed to contribute to primitive and transient definitive hematopoiesis in the embryo (Nakano et al, 2013). Finally, expression of the human NKX2-5 gene occurs in a subset of paediatric T and B cell acute lymphoblastic leukaemias defined by a t(5;14) translocation (Nagel et al, 2003; Su et al, 2008). …”

Homeobox protein TLX3 activates miR-125b expression to promote T-cell acute lymphoblastic leukemia

“…Alternative rearrangements of the 5q35 locus affecting expression of TLX3 have also been reported. [7][8][9] How TLX3 contributes to leukemia development is still elusive. Recent studies suggest that TLX3 as well as its homolog TLX1 may be recruited by the ETS1 transcription factor to the core of the T-cell receptor a (TCRa) enhancer (Ea) and repress its activity.…”