Curr Hematol Malig Rep (2012) 7:133–143 initially identified in the rare chromosomal translocation t (7;9)(q34;q34.3) that fuses the intracellular form of NOTCH1 to the TCR beta and leads to the expression of TAN1, a truncated and constitutively activated form of NOTCH1; subsequently, activating or loss of function muta- tions has been identified in more than 50 % of T-ALL cases, representing the most common alteration in T-ALL. The high frequency of NOTCH1 mutations in T-ALL has sparked an interest in the development of anti-NOTCH1 targeted therapies for the treatment of T-ALL. Other mutated genes in T-ALL are WT1, NRAS, the negative regulator of the RAS pathway, NF1 that is inactivated because of dele- tions or mutations [80], and rarely FLT3 [81, 82] and PTPN2 [83], that are affected by activating mutations and focal deletions, respectively. All these genes play crucial roles as regulators and alterations in their function may affect critically different signal transduction pathways. Of note, identification of 6q15-16.1 deletion containing CAS- P8AP2 gene represents a novel prognostic factor that defines a high-risk group (Table 2) [84]. Prognostic Factors Based on Next-Generation Sequencing Technology Using exon capture of chromosome X a recent study by Van Vlierberghe and colleagues [85] identified inactivating muta- tions of the X-linked plant homeodomain finger 6 (PHF6) in 16 % of pediatric and 38 % of adult T-ALL cases. PHF6 139 mutations were almost exclusively found in male and were associated with leukemias driven by aberrant expression of TLX1 and TLX3. Although the prognostic significance remains to be determined, PHF6 has emerged as a new X-linked tumor suppressor in T-ALL. Recently, the application of whole- genome sequencing (WGS) to the characterization of “early T-cell precursor” (ETP) ALL, that comprises up to 15 % of T- ALL and is associated with a high risk of treatment failure, has provided potential new molecular targets for therapy [86]. Zhang and colleagues [86] performed WGS of 12 ETP ALL cases identifying activating mutations in genes regulating cy- tokine receptor and RAS signaling, such as NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3, and BRAF (67 %), inacti- vating lesions disrupting hematopoietic development, such as GATA3, ETV6, RUNX1, IKZF1, and EP300 (58 %), and histone-modifying genes, such as EZH2, EED, SUZ12, SETD2, and EP300 (48 %). Moreover, they identified new targets of recurrent mutation in DNM2, ECT2L, and RELN genes. Impor- tantly, the gene expression profile of ETP ALL resulted similar to that of normal and myeloid leukemia hematopoietic stem cells, suggesting the possibility that myeloid-directed therapies might improve the poor outcome of ETP ALL. Conclusions Thanks to the use of SNP microarray-based technology, extensive candidate gene sequencing, and whole genome/ Table 2 Novel recurring genetic alterations occurring in T-progenitor ALL and their correlation with outcome Sequence mutations Deletions or sequence mutations 6–8 % of T-ALL Gene name Alteration NOTCH1 Sequence mutations CDKN2A/B Deletions FBXW7 PTEN CDKN1A 6q15-16.1 PHF6 WT1 LEF1 JAK1 FLT3 PTPN2 Deletions or sequence mutations Deletion Deletions or sequence mutations Frameshift mutations Focal deletions or sequence mutations Sequence mutations Internal tandem duplication Deletion Frequency ~50 % of T-ALL ~20 % of T-ALL 30–70 % of T-ALL 12 % of T-ALL 12 % of T-ALL 16 % of pediatric T-ALL cases; 38 % of adult T-ALL cases 13 % of pediatric T-ALL cases; 12 % of adult T-ALL cases 15 % of pediatric T-ALL cases 18 % of adult T-ALL cases 4 % of adult T-ALL cases; 3 % of pediatric T-ALL cases 6 % of T-ALL Prognosis Associated with favorable outcome in children Associated with favorable outcome in children Associated with poor response to chemotherapy and resistance to pharmacological inhibition of NOTCH1 Associated with poor outcome in adult and children T-ALL To be investigated Associated with poor outcome Associated with reduced overall survival No association with outcome Associated with younger age and a trend toward a better overall survival Associated with reduced disease-free survival and overall survival No association with outcome Down-regulation of PTPN2 expression results in prolonged survival of ALL-SIL cells after imatinib treatment Reference [89–92] [78, 91, 92] [76, 93] [94, 95] [84, 96] [84] [85] [97, 98] [99] [72] [81, 82] [100]