To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase–mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease.

/pdf/discovery-and-prioritization-of-somatic-mutations-in-diffuse-3tfimq7aw5.pdf

Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(12)62187-4.pdf

Acute lymphoblastic leukaemia.

Purpose To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Methods A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. Results With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome–positive, and Philadelphia chromosome–like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic p...

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration

Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.

/pdf/the-genomic-landscape-of-pediatric-and-young-adult-t-lineage-4lj166zvr1.pdf

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5′ untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5′ UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase. The translation of many messenger RNAs that encode important oncogenes and transcription factors depends on the eIF4A RNA helicase to resolve G-quadruplex structures, implying eIF4A inhibition as an effective cancer therapy. The expression of some oncoproteins is regulated at the translational level. Hans-Guido Wendel and colleagues show that a subset of oncoprotein- and transcription factor-encoding mRNAs that are dependent on the translation initiation factor eIF4A contain a G-quadruplex-forming structure in their 5′ untranslated regions. These findings explain why silvestrol, a plant-derived anticancer agent that targets eIF4A-dependent translation, is not generally toxic but can be well tolerated except in cancer cells which are dependent on the activities of these proteins. In a separate study in this issue, Stephan Vagner and colleagues show that inhibition of eIF4F cooperates with BRAF inhibitors in reducing the growth of melanomas linked to BRAF mutations.

RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

Integrated Transcript and Genome Analyses Reveal NKX2-1 and MEF2C as Potential Oncogenes in T Cell Acute Lymphoblastic Leukemia

Background PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors.

Design and Methods The impact of PTEN , PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols.

Results PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN -splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL - or LMO -rearranged leukemia but nearly absent in TLX3 -rearranged patients ( P =0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations ( P =0.006) or had weak NOTCH1-activating mutations ( P =0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients ( P =0.005).

Conclusions PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors.

/pdf/the-significance-of-pten-and-akt-aberrations-in-pediatric-t-xp3vplpmr1.pdf

The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia

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Integrated Transcript and Genome Analyses Reveal NKX2-1 and MEF2C as Potential Oncogenes in T Cell Acute Lymphoblastic Leukemia

The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia