Combinations of post-translational histone modifications shape the chromatin landscape during cell development in eukaryotes. However, little is known about the modifications exactly delineating functionally engaged regulatory elements. For example, although histone H3 lysine 4 mono-methylation (H3K4me1) indicates the presence of transcriptional gene enhancers, it does not provide clearcut information about their actual position and stagespecific activity. Histone marks were, therefore, studied here at genomic loci differentially expressed in early stages of T-lymphocyte development. The concomitant presence of the three H3K4 methylation states (H3K4me1/2/3) was found to clearly reflect the activity of bona fide T-cell gene enhancers. Globally, gain or loss of H3K4me2/3 at distal genomic regions correlated with, respectively, the induction or the repression of associated genes during T-cell development. In the Tcrb gene enhancer, the H3K4me3-to-H3K4me1 ratio decreases with the enhancer's strength. Lastly, enhancer association of RNApolymerase II (Pol II) correlated with the presence of H3K4me3 and Pol II accumulation resulted in local increase of H3K4me3. Our results suggest the existence of functional links between Pol II occupancy, H3K4me3 enrichment and enhancer activity.

Purpose Early thymic precursor (ETP) acute lymphoblastic leukemia (ALL) is an immunophenotypically defined subgroup of T-cell ALL (T-ALL) associated with high rates of intrinsic treatment resistance. Studies in children have shown that the negative prognostic impact of chemotherapy resistance is abrogated by the implementation of early response-based intensification strategies. Comparable data in adults are lacking. Patients and Methods We performed comprehensive clinicobiologic, genetic, and survival analyses of a large cohort of 213 adult patients with T-ALL, including 47 patients with ETP-ALL, treated in the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia) -2003 and -2005 studies. Results Targeted next-generation sequencing revealed that the genotype of immunophenotypically defined adult T-ALL is similar to the pediatric equivalent, with high rates of mutations in factors involved in cytokine receptor and RAS signaling (62.2%), hematopoietic development (29.7%), and chemical modification of histones (48.6%). In contrast to pediatric cases, mutations in DNA methylation factor genes were also common (32.4%). We found that despite expected high levels of early bone marrow chemotherapy resistance (87%), the overall prognosis for adults with ETP-ALL treated using the GRAALL protocols was not inferior to that of the non-ETP-ALL group (5-year overall survival: ETP, 59.6%; 95% CI, 44.2% to 72.0% v non-ETP, 66.5%; 95% CI, 58.7% to 73.2%; P = 0.33) and that allogeneic stem-cell transplantation had a beneficial effect in a large proportion of patients with ETP-ALL. Conclusion Our results suggest that the use of response-based risk stratification and therapy intensification abrogates the poor prognosis of adult ETP-ALL.