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...

To accurately estimate the incidence of HOX11L2 expression, and determine the associated cytogenetic features, in T-cell acute lymphoblastic leukemia (T-ALL), the Groupe Franç ais de Cytogé né tique Hé matologique (GFCH) carried out a retrospective study of both childhood and adult patients. In total, 364 patients were included (211 children p15 years and 153 adults), and 67 (18.5%) [47 children (22.4%) and 20 adults (13.1%)] were shown to either harbor the t(5;14)q35;q32) translocation or express the HOX11L2 gene or both. Most of the common hematological parameters did not show significant differences within positive and negative populations, whereas the incidence of CD1a+/CD10+ and cytoplasmic CD3+ patients was significantly higher in positive than in negative children. Out of the 63 positive patients investigated by conventional cytogenetics, 32 exhibited normal karyotype, whereas the others 31 showed clonal chromosome abnormalities, which did not include classical T-ALL specific translocations. Involvement of the RANBP17/HOX11L2 locus was ascertained by fluorescence in situ hybridization in six variant or alternative (three-way translocation or cytogenetic partner other than 14q32) translocations out of the 223 patients. Our results also show that HOX11L2 expression essentially occurs as a result of a 5q35 rearrangement, but is not associated with another identified T-ALL specific recurrent genetic abnormality, such as SIL-TAL fusion or HOX11 expression.

Translocations involving MYC are rare in chronic lymphocytic leukemia (CLL), and up to now, their prognostic significance remains unclear. We report the characteristics of 21 patients with CLL and nine patients with prolymphocytic leukemia (PLL), diagnosed in multiple centers (n = 13), which showed an MYC translocation demonstrated by fluorescence in situ hybridization. The prevalence was estimated to be <1%. Advanced age and male predominance were observed. Morphological analysis frequently revealed the presence of prolymphocytes. A typical "CLL-immunophenotype" was found in four of nine cases with PLL. Moreover, CD5 and CD23 were frequently expressed in PLL. The latter findings are atypical for PLL and may suggest transformation or progression of an underlying CLL. MYC translocations were frequently observed with concomitant adverse cytogenetic markers, such as del(11q) (n = 8/30) and/or del(17p)/monosomy 17 (n = 7/30). In addition, the presence of unbalanced translocations (n = 24 in 13/30 cases) and complex karyotype (n = 16/30) were frequent in cases with MYC translocations. Altogether, del(17p)/monosomy 17, del(11q), and/or complex karyotype were observed in 22 of 30 patients. Survival outcome was poor: the median time to treatment was only 5 months, and overall survival (OS) from clinical diagnosis and from genetic detection was 71 and 19 months, respectively. In conclusion, CLL/PLL with MYC translocations is a rare entity, which seems to be associated with adverse prognostic features and unfavorable outcome.

Human gliomas including astrocytomas and oligodendrogliomas are defined as being composed of neoplastic astrocytes and oligodendrocytes respectively. Here, on the basis of in vitro functional assays, we show that gliomas contain a mixture of glial progenitor cells and their progeny. We have set up explant cultures from pilocytic astrocytomas, glioblastomas and oligodendrogliomas and studied antigens that characterize glial lineage, from the precursor cells (glial restricted precursors and oligodendrocyte-type2-astrocyte/oligodendrocyte precursor cells expressing the A2B5 ganglioside) to the differentiated cells (oligodendrocyte and type-1 and type-2 astrocytes). All tumoral explants contain A2B5+ cells and can generate migrating cells with distinctive functional properties according to glioma subtypes. In pilocytic astrocytomas, very few migrating cells are dividing and can differentiate in type-2 astrocytes or towards the oligodendrocyte lineage. In glioblastomas, most migrating cells are dividing, express A2B5 or glial fibrillary acid protein (GFAP) and can generate oligodendrocytes and type-1 and type-2 astrocytes in appropriate medium. Oligodendroglioma explants are made by actively dividing glial precursor cells expressing A2B5 or PSA-NCAM. Only few cells can migrate and differentiation towards oligodendrocyte lineage does not occur. Isolated A2B5+ cells from both glioblastomas and oligodendrogliomas showed similar genetic alterations as the whole tumour. Therefore, pilocytic astrocytomas contain slowly dividing oligodendrocyte-type2-astrocyte/oligodendrocyte precursor cells in keeping with their benign behaviour whereas both glioblastomas and oligodendrogliomas contain neoplastic glial restricted precursor cells. In oligodendrogliomas, these cells are trapped in undifferentiated and proliferating state. The precursor cells properties present in gliomas give new insight into their histogenesis and open up new avenues for research in the field of gliomagenesis.

Key Points B-PLL is tightly linked to MYC aberrations (translocation or gain) and 17p (TP53) deletion. Cases of B-PLL with MYC aberration and 17p (TP53) deletion have the worst prognosis.