[HTML][HTML] Role of TLX1 in T-cell acute lymphoblastic leukemia pathogenesis

I Riz, TS Hawley, H Johnston… - British journal of …, 2009 - ncbi.nlm.nih.gov
I Riz, TS Hawley, H Johnston, RG Hawley
British journal of haematology, 2009ncbi.nlm.nih.gov
The diverged homeobox gene TLX1 (for T-cell leukemia homeobox 1, previously known as
HOX11 or TCL3) is activated in⁓ 5-10% of childhood and up to 30% of adult T-cell acute
lymphoblastic leukemia (T-ALL) cases, most frequently by t (10; 14)(q24; q11) and t (7;
10)(q35; q24) chromosomal translocations which juxtapose the intact TLX1 coding region
downstream of T cell receptor (TCR) δ (TRD@) or TCRβ (TCRB) gene regulatory
sequences. TLX1+ T-ALL samples are virtually all arrested at the early cortical (CD1+) …
The diverged homeobox gene TLX1 (for T-cell leukemia homeobox 1, previously known as HOX11 or TCL3) is activated in⁓ 5-10% of childhood and up to 30% of adult T-cell acute lymphoblastic leukemia (T-ALL) cases, most frequently by t (10; 14)(q24; q11) and t (7; 10)(q35; q24) chromosomal translocations which juxtapose the intact TLX1 coding region downstream of T cell receptor (TCR) δ (TRD@) or TCRβ (TCRB) gene regulatory sequences. TLX1+ T-ALL samples are virtually all arrested at the early cortical (CD1+) CD4+CD8+“double-positive”(DP) stage of thymocyte development (Ferrando et al, 2002; Asnafi et al, 2004).
We previously showed that retroviral expression of TLX1 in primary murine hematopoieticrepopulating cells induced T-ALL-like malignancies in engrafted mice (Hawley et al, 1997). However, the murine model system did not perfectly reproduce the phenotype of human TLX1+ T-ALL (Owens et al, 2006). Furthermore, a low penetrance and long latency of tumor induction indicated the requirement for additional neoplastic mutations, consistent with a multistep mechanism of leukemogenesis (De Keersmaecker et al, 2006; Van Vlierberghe et al, 2008). In this latter regard, it has been found that the CDKN2A tumor suppressor locus is inactivated by homozygous or hemizygous deletion in most cases of TLX1+ disease (Sulong et al, 2008). Also,> 50% of all T-ALL cases—including TLX1+ samples—harbor activating mutations in the NOTCH1gene (Weng et al, 2004). Other recent work has identified two variant ABL1 fusion genes encoding constitutively activated tyrosine kinases in many TLX1+ T-ALL cases (De Keersmaecker et al, 2006); and tandem duplication of the MYB transcription factor oncogene has also been described (Lahortiga et al, 2007). The importance of these cooperative genetic aberrations in the multistep transformation of TLX1+ T-ALL is underscored by the ALL-SIL cell line (DSMZ no. ACC 511)(Riz & Hawley, 2005), which carries all of these alterations (summarized in Owens et al, 2006).
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