Cancer Report

Cancer : T-lineage acute lymphoblastic leukemia (T-ALL)
Cancer Name T-lineage acute lymphoblastic leukemia (T-ALL)
Cancer Alias T-cell ALL
Description Most of the recurrent abnormalities in T-ALL are different from those associated with B-lineage ALL. Clinical aspects of the main chromosomal abnormalities observed by conventional cytogenetics are herein described. The numerous oncogenes involved in T-ALL were first characterized by cloning of recurrent chromosomal abnormalities. Subsequently, distinct oncogenic T-ALL subgroups were defined by modern molecular methods. A brief description of the novel cryptic genetic lesions that are intertwined with the molecular cytogenetics of T-cell disease is presented here.
Clinics and Pathology
Etiology Immunophenotypic and gene expression analyses of T-ALL cells have revealed heterogeneity that is partially related to arrest at distinct stages of development. Initial cytogenetics studies of T-ALL cases showed nonrandom breakpoints within the following three T-cell receptor (TCR) gene clusters: TRA@ (TCRA), TRD@ (TCRD) locus (14q11.2), or TRB@ (TCRB) locus (7q34). The TCR breakpoints were present in about 30% to 35% of T-ALL cases. The TRG@ (TCRG) locus (7p14) may be restricted to T-cell ALL in patients with ataxia telangiectasia. During T-cell differentiation, these four loci undergo structural rearrangement that is analogous to the rearrangement of immunoglobulin genes during B-cell development.

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.

Epidemiology Among acute leukemia, T-ALL accounts for about 15% of pediatric cases and 20% of adults cases. As detected by conventional cytogenetic methods, patients with T-ALL have a smaller percentage of abnormal clones (60%-70%) than do patients with B-lineage ALL (80%-90%). Tetraploidy is observed in about 3% of patients with T-ALL, but it has no known prognostic significance. Cytogenetic abnormalities that are common in B-cell ALL (e.g., high-hyperdiploidy) are uncommon in T-cell ALL. Many of the translocations seen in T-ALL are recurrent but with a low frequency.

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.

Prognosis The historically unfavorable outcome of patients with T-ALL has recently improved through the use of highly effective treatment protocols. T-ALL is now treated the same way as high-risk B-progenitor ALL. With appropriately intensive therapy, children with T-ALL have an outcome similar to that of children with B-precursor ALL, i.e., the estimated 5-year event-free survival (EFS) is 75% to 80%. Nevertheless, patients with T-ALL remain at increased risk for remission induction failure, early relapse, and isolated CNS relapse. In a recent study of adolescents with ALL, no significant difference in outcome of T-ALL was found on the basis of age; older patients did as well as younger ones.

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.

Related Genes
Gene Symbol TOPORS
Description From COSMIC:
Gene Symbol RB1
Description From COSMIC:
Gene Symbol OLIG2
Description From cancer gene census of CGP:
Gene Symbol SIL
Description From cancer gene census of CGP:
Gene Symbol ABL1
Description From cancer gene census of CGP:
Gene Symbol N-RAS
Description From COSMIC:
Gene Symbol TRA
Description From cancer gene census of CGP:
Gene Symbol TAL2
Description From cancer gene census of CGP:
Gene Symbol AF4P12
Description B-ALL
Gene Symbol PICALM
Description From cancer gene census of CGP, OMIM
Gene Symbol LYL1
Description From cancer gene census of CGP:
Gene Symbol NUP214
Description From cancer gene census of CGP:
Gene Symbol PTENP1
Description From COSMIC:
Gene Symbol TRB
Description From cancer gene census of CGP:
Gene Symbol TLX1
Description From cancer gene census of CGP:
Gene Symbol FLT3
Description From COSMIC:
Gene Symbol TLX3
Description From cancer gene census of CGP:
Gene Symbol TCL1B
Description From cancer gene census of CGP:
Gene Symbol STK11
Description From COSMIC:
Gene Symbol BCL11B
Description From cancer gene census of CGP:
Gene Symbol WT1
Description From COSMIC:
Gene Symbol K-RAS
Description From COSMIC:
Gene Symbol CDKN2A
Description From COSMIC:
Gene Symbol VRK1
Gene Symbol LMO1
Description From cancer gene census of CGP:
Gene Symbol SMARCB1
Description From COSMIC:
Gene Symbol LMO2
Description From cancer gene census of CGP:
Gene Symbol NOTCH1
Description From COSMIC, cancer gene census of CGP
Gene Symbol TNFSF4
Description From Atlas of Genetics and Cytogenetics in Oncology and Haematology:
Gene Symbol JAK2
Description From COSMIC:
Gene Symbol PIK3CA
Description From COSMIC:
Gene Symbol MSH6
Description From COSMIC:
Gene Symbol LCK
Description From cancer gene census of CGP:
Gene Symbol RAP1GDS1
Description From cancer gene census of CGP:
Gene Symbol TAL1
Description From cancer gene census of CGP
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Source and Citation
Source Atlas of Genetics and Cytogenetics in Oncology and Haematology
Citation Raimondi SC . T-lineage acute lymphoblastic leukemia (T-ALL). Atlas Genet Cytogenet Oncol Haematol. May 2007 .