138 T-Progenitor Acute Lymphoblastic Leukemia Prognostic Factors Based on Cytogenetics T-ALL is a malignant disorder of T-cell lymphoid progenitor cells that affects 15 % of children and 25 % of adults with ALL. Structural chromosomal aberrations are identified in approximately 50 % of cases and frequently involve the juxtaposition of strong promoter and enhancer elements from T-cell receptor (TCR) genes with transcription factor genes as consequence of an illegitimate event during V(D)J recombination in normal T-cell development. This leads to the aberrant expression of the fusion partners resulting in thymocytes differentiation block at various stages of maturation. TCR Gene Rearrangements The most common rearrangements include TCR alpha/delta chain at 14q11.2, TCR beta chain at 7q34, and TCR gamma chain at 7p14. With few exceptions, the involved gene on the partner chromosome encodes a cell cycle inhibitor or a transcription factor whose expression is deregulated or acti- vated as a result of the rearrangement. TAL1 (1p32) is ectopically expressed in T-ALL as consequence of t(1;14) (p32;q11) [59] (3 % in childhood T-ALL) and more fre- quently as a consequence of the intrachromosomal deletion resulting in SIL-TAL1 fusion gene, while LYL1 (19p13), TAL2 (9q32), and BHLH1 (21q22) are up-regulated in the rare translocations t(7;19)(q34;p13), t(7;9)(q34;q32), and t (14;21)(q11;q22), respectively. Their aberrant expression may contribute to leukemia through the formation of heter- odimers with class I basic helix-loop-helix members that regulate T-cell specific genes, with consequent differentia- tion and proliferation impairment. LIM domain only genes LMO1 (11p15) and LMO2 (11p13) are involved in t(11;14) (p15;q11) and t(11;14)(p13;q11) with TCR alpha/delta loci and in translocations with TCR beta. LMO abnormal ex- pression associates with deregulation of LYL1 and TAL1, even in absence of specific translocations [60]. The homeo- box (HOX) genes are a highly conserved family of tran- s c r i p t i o n f a c t o r s t h a t p l a y a n i m p o r t a n t r o l e i n morphogenesis during embryonic development and in nor- mal hemopoiesis [61]. The inv(7)(p15q34) and t(7;7)(p15; q34) bring the TCR beta regulatory elements in the vicinity of the HOXA genes cluster disrupting the normal regulatory elements of the cluster with subsequent up-regulation, espe- cially of HOXA9, HOXA10, and HOXA11 [62, 63]. TLX1 (HOX11) is expressed at high level in more than 30 % of adult T-ALL as consequence of t(10;14)(q24;q11) and t (7;10)(q34;q24), while TLX3 (HOX11L2) is involved in t (5;14)(q35;q32) with the fusion partner BCL11B in about 20 % of children and 4 % of adults [64]. Additional genes Curr Hematol Malig Rep (2012) 7:133–143 rarely involved in TCR loci rearrangements are LCK [65], CCND2 [66], and IRS4 [67]. Non-TCR Loci A variety of cytogenetic abnormalities can occur in T-cell ALL that do not involve the TCR loci. These include del (6q), t(11q23) (MLL gene), t(14q32), trisomy 8, and t (10;11). A favorable prognostic correlation has been assessed for t(10;14), which is extremely rare in adult patients, and more frequent in the pediatric subset. Trisomy of chromosome 8 and monosomy of chromosome 7 usually carry a bad prognosis [68]. The cryptic deletion del(9) (q34.11q34.13) results in the SET-NUP214 fusion product, which transcriptionally activates specific members of the HOXA cluster maybe contributing to T-ALL pathogenesis by the inhibition of T-cell maturation [69]. The ABL1 cyto- plasmic tyrosine kinase plays a role in T-cell signaling, leading to the induction of IL-2 production and proliferation following TCR activation [70]. ABL1 fusion genes can be identified in about 8 % of T-ALL. EML1-ABL1 fusion due to a cryptic t(9;14)(q34;q32), BCR-ABL1 t(9;22)(q34;q11), and ETV6-ABL1 t(9;12)(q34;p13) are seldom reported chi- meric genes in T-ALL, although if frequent in other hema- tologic malignancies. In contrast, the most frequent and strictly associated alteration with T-ALL is the NUP214- ABL1 fusion identified in 6 % of cases, in both children and adults, also if it is not clear its prognostic relevance [71]. JAK2 resulted constitutively activated in the rare t(9;12) (p24;p13) encoding ETV6-JAK2 fusion oncoprotein, while JAK1 is widely mutated in adult T-ALL (18 %) and less in children (3 %), and associates with a poor response to therapy [72]. Finally, a recent study identified a novel fusion partner of ETV6 in one T-ALL patient, harboring ETV6- ARNT t(1;12)(q21;p13) [73]. Prognostic Factors Based on Genomic Profiling On the basis of gene expression profiling, T-ALL cases can be classified into major subgroups that are indicative of leukemic arrest at specific stages of normal thymocyte de- velopment (HOX11+ early cortical thymocytes; LYL1+ early pro-T thymocytes; TAL1+ late cortical thymocytes) and have clinical relevance, because they are associated with a favor- able or worse prognosis [60]. Using SNP array platforms, many novel genomic alterations have recently been identi- fied, including focal deletions of RB1 [5], duplications of the proto-oncogene MYB [5, 74], deletion of 9p21.2 in more than 70 % of patients [75], deletion and mutation of PTEN [5, 76], and deletion or mutation of the U3 ubiquitin ligase FBXW7 [77, 78]. Thus far, mutations of NOTCH1 and FBXW7 have generally been associated with a favorable prognosis [79]. NOCTH1 role in leukemogenesis was