Cumulative evidence indicates that MYC, one of the major downstream effectors of NOTCH1, is a critical component of T-cell acute lymphoblastic leukemia (T-ALL) oncogenesis and a potential candidate for targeted therapy. However, MYC is a complex oncogene, involving both fine protein dosage and cell-context dependency, and detailed understanding of MYC-mediated oncogenesis in T-ALL is still lacking. To better understand how MYC is interspersed in the complex T-ALL oncogenic networks, we performed a thorough molecular and biochemical analysis of MYC activation in a comprehensive collection of primary adult and pediatric patient samples. We find that MYC expression is highly variable, and that high MYC expression levels can be generated in a large number of cases in absence of NOTCH1/FBXW7 mutations, suggesting the occurrence of multiple activation pathways in addition to NOTCH1.
IntroductionT-cell acute lymphoblastic leukemias (T-ALL) are malignant proliferations of T-cell precursors that represent 10% of pediatric and 25% of adult ALL. 1 Although treatment outcome has significantly improved in the last decade, ϳ 30% of patients relapse and remain of dismal prognosis, stressing the critical importance of gaining further insights on the molecular pathways controlling malignant transformation and drug resistance. However, a major obstacle in deciphering such pathways and implementing targeted therapy strategies resides in the fact that T-ALLs constitute a particularly heterogeneous and complex group of disease, resulting from numerous combinations of multigenic aberrations and oncogenic cooperation. 2 To date, the deregulation of Ͼ 30 distinct oncogenes and tumor suppressors (TS) has been reported, occurring through a large diversity of genomic aberrations and epigenetic deregulations. All such mechanisms are not functionally equivalent, 3 and distinct modes of oncogenic activation may drive different oncogenic processes, and generate distinct subtypes of prognostic significance. Some oncogenes (eg, TLX1, TAL1) appear to be mutually exclusive (type A) and delineate distinct subgroups of prognostic significance, correlating with specific stages of thymocyte developmental arrest (immature/DN, intermediate/ pre-␣, and mature/T-cell receptor␣ ϩ , respectively). [4][5] By contrast, other deregulations, such as loss of CDKN2A/p14ARF, or constitutive NOTCH1 activation, are found in a large proportion of cases and irrespective of subgroups (type B), 2 indicating a more universal role for these alterations in T-ALL pathogenesis, and pointing to attractive therapeutic targets. One such target is NOTCH1 and downstream pathways. Indeed, the key finding that Ͼ 50% of T-ALL cases display gain-of-function NOTCH1 mutations (NOTCH1 m ) initially held great promise for targeted therapy through the use of ␥-secretase inhibitors (GSI). 6 However, the frequent occurrence of GSI-resistance (GSI R ) has revealed an unsuspected complexity of the oncogenic network signaling downstream of NOTCH1. 6-8 Among the numerous target genes and pa...
