1.Department of pathology, St. Jude Childrens Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105-2794, USA
The TCR promoter and enhancer elements are juxtaposed to a relatively small number of developmentally important genes that encode transcription factors leading to T-cell malignancies. The chromosomal aberrations that affect the TCR loci were among the first to be reported in T-ALL. Subsequently, these and other rarer translocations facilitated the identification of genes that are altered in T-ALL, many of which are also transcriptionally activated without evidence of any detectable chromosomal rearrangement affecting these loci. In summary, the ectopic expression of TAL1(SCL),LYL1, LMO1, LMO2, TLX1(HOX11), and TLX3 (HOX11L2), NOTCH1-activating mutations, and CDKN2-inactivating deletions are among the most prevalent causes of human T-ALL.
A high number of T-ALL cases have cryptic abnormalities, as shown by fluorescent in situ hybridization (FISH) or other molecular methods. In some instances, this occurs because some of the loci involved in oncogenic rearrangements of T-ALL have a near-telomeric location that generates subtle exchanges in DNA material, and these changes subsequently cause the cryptic translocations. As many as 80% of patients with T-ALL have cryptic deletions of the putative tumor suppressor gene CDKN2A (INK4A) (9p21), and as many as 60% have cryptic deletions of TAL1 (1p32). Other genes such as TLX1 (HOX11) (10q24) and NOTCH1 (9q34) are activated at a much higher frequency than expected from cytogenetic studies alone; thus, simultaneous dysregulation of different signaling pathways may contribute to the multistep pathogenesis of T-ALL subgroups.
At present, there are no genetic markers in T-ALL that reliably predict treatment response or outcome. Gene expression analysis has revealed the prognostic significance of T-ALL oncogenes and the stage of thymocyte differentiation in which they are expressed. Some genetic markers have been shown to be of clinical relevance in a small series of pediatric patients with T-ALL: TLX1(HOX11)+ was associated with favorable outcome, and TAL1+ and LYL1+ were associated with unfavorable outcome. A favorable prognosis was also found with TLX1(HOX11)+ in adult T-ALL, possibly due to downregulation of antiapoptotic genes. The poor prognosis associated with T-ALL subtypes expressing TAL1 or LYL1 is thought to be caused by the concomitant upregulation of antiapoptotic genes that confer resistance to chemotherapy.
In early studies, the overexpression of TLX3(HOX11L2) was associated with poor prognosis; however, similar, more recent studies have not confirmed such findings. This difference is probably a reflection of the current aggressive treatments that have improved the therapeutic response in this subgroup of T-ALL. Therefore, the clinical significance of genetic lesions in T-ALL remains largely unknown. The prognostic significance of T-ALL subtypes most likely depends on the type and intensity of the treatment administered. The development of targeted therapy for T-ALL might be contentious, given the simultaneous presence and the high prevalence of some genetic lesions affecting T-ALL.
TRB@ (7q34)Conventional cytogenetic analysis revealed that chromosomal abnormalities affecting 7q34 (TRB@) occur in 5% to 8% of T-ALL cases with an abnormal karyotype. Recent molecular cytogenetics studies have revealed a higher incidence of TRB@ locus rearrangements (about 20% of all T-ALL cases). This finding demonstrates that the frequency of TRB@ rearrangements is similar to that of TRA@ (14q11.2) (about 24% of all T-ALL cases). Simultaneous rearrangements targeting both the TRB@ and TRA@ loci were observed in five of 126 (4%) patients with T-ALL, possibly reflecting the higher susceptibility for errors in VDJ recombination.
TRG@ (7p14))The TRG@(TCRG) locus (7p14) may be restricted to T-cell tumors in patients with ataxia telangiectasia. The TRG@ locus is not involved in translocations in T-ALL. Historically, it was thought that the inv(7)(p15;q34) or t(7;7)(p15;q34) juxtaposed TRB@ to TRG@, but recently it was shown that the TRB@-HOXA fusion is generated by such rearrangements. One exception was a t(1;7)(p31-32;p13) in a 16 year-old male patient who had precursor T-cell lymphoblastic leukemia/lymphoma. This rearrangement was identified during the evaluation of FISH probes to detect TCR breakpoints. It was speculated that the breakpoint at 1p may have involved the TAL1 or LCK oncogenes.
TRA@ or TRD@ (14q11.2)Among the most common chromosomal abnormalities observed by conventional cytogenetics, those associated with T-ALL are chromosome 14 alterations in which the breakpoint is located at 14q11.2. By conventional cytogenetics, this abnormality represents about 17% of all T-ALL cases (Table 1). By molecular cytogenetics studies, the incidence of TRA@/TRD@ rearrangements is about 24% of all T-ALL cases.
NON-TCR GENETIC LESIONS IN T-ALL
In addition to conventional cytogenetic studies, molecular techniques that are more reliable, rapid, and sensitive are needed to detect multiple genetic lesions associated with T-ALL. The improved characterization of T-ALL genetic subgroups may facilitate the development of targeted gene therapy for those patients with refractory disease and less toxic therapy for those with responsive disease.
In recent years, the introduction of more intensive therapy has improved the overall outcome of patients with T-ALL, as indicated in the following landmark discoveries: Most of the recurrent abnormalities in T-ALL are different from those associated with B-lineage ALL.
Susana C Raimondi
T-lineage acute lymphoblastic leukemia (T-ALL)
Atlas Genet Cytogenet Oncol Haematol. 2007-05-01
Online version: http://atlasgeneticsoncology.org/haematological/1374/t-lineage-acute-lymphoblastic-leukemia-(t-all)