Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia

Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, PPeer reviewe

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

© 2019 Elsevier Inc. Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death. Sin-Chan et al. uncover a C19MC-LIN28A-MYCN super-enhancer-dependent oncogenic circuit in embryonal tumors with multilayered rosettes (ETMRs). The circuit entraps an early neural lineage network to sustain embryonic epigenetic programming and is vulnerable to bromodomain inhibition, which promotes ETMR cell death

The molecular basis of E2A-HLF induced precursor-B cell acute lymphoblastic leukaemia in childhood

Translocation t(17;19)(q21-22;p13) occurs in a small subset (0.5-1%) of childhood precursor B (Pre-B) cell acute lymphoblastic leukaemia (ALL), and produces a chimeric transcription factor, E2A-HLF, which is a fusion oncoprotein. E2A-HLF expression confers a poor clinical outcome with a high risk of refractory relapse, and is associated with distinctive clinical features. Patients in the UK, currently diagnosed with this translocation are being stratified to receive “high risk” therapy protocol, including allogeneic bone marrow transplantation. Our group has identified six patients in the UK and Ireland with t(17;19)(q21-22;p13), and three from other parts of the world, in the last six years. These are in addition to the previously identified fourteen patients from a worldwide literature search. This extended patient base, coupled with poor outcome, necessitates an improved understanding of this translocation. We aimed to study the molecular aetiology of the leukaemia, and establish the molecular pathways involved. To study the molecular aetiology, we analysed six patients’ genomic DNA samples at diagnosis and/or relapse and the DNA extracted from their corresponding Guthrie cards (neonatal blood spots) by employing PCR based methods. We identified a type I genomic rearrangement in two of the patients, and a type II in one patient, at the region of the genomic fusion. Two other patients were identified with a unique type of rearrangement not classifiable as either type I or II. The mechanism of translocation in our patient samples, suggested an aberrant V(D)J rearrangement at the breakpoint region. Analysis of the Guthrie cards indicated the possibility of a prenatal origin for this translocation. We developed an in vitro inducible expression system (Tet-off) for E2A-HLF expression to understand the molecular pathways activated by this translocation. Murine foetal liver haematopoietic progenitor cells (HPC) were transduced with retroviral vectors expressing E2A-HLF in myeloid and lymphoid cultures. This allowed us to identify a gene expression profile for E2A-HLF from immortalised foetal liver HPC in methylcellulose and liquid culture. The downstream target genes of E2A-HLF identified in our study included Il15, Cd28, Kdr, Ccl9 and Ccl6. Further validation has been carried out on Il15 as a potential target of E2A-HLF