Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome ...sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.
Diagnosis of invasive aspergillosis (IA) remains a challenge as the clinical manifestations are not specific, and a histological diagnosis is often unfeasible. The 2002 European Organization for ...Research and Treatment of Cancer (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria for classification of cases into possible, probable or proven were revised in 2008. Our objective was to analyze the impact of these revisions on the diagnosis of IA. A retrospective analysis of 589 high risk patient-episodes revealed that 125 of 155 'possible' (81%) and 12 of 16 'probable' (75%) cases of IA should be changed to 'non-classifiable' when the new criteria were applied. We concluded, as expected, that the 2008 EORTC/MSG revised definitions reduced the number of cases classified as 'possible' IA, but additionally, there has been a dramatic reduction in 'probable' cases. These changes have significant implications on the interpretation of clinical trial data based on EORTC/MSG classifications.
The gene-expression profiling score described by Huet and colleagues is the latest attempt at addressing this challenge, leveraging gene expression data from a discovery series of 134 fresh-frozen ...tumours from patients with follicular lymphoma before they started treatment in the randomised PRIMA trial, a study with a respectable follow-up of 6 years.The predictive power of this new 23-gene expression model (5-year progression-free survival of 26% (95% CI 16–43) in the high-risk group vs 73% (64–83) in the low-risk group) uses a different strategy to the previously reported m7-FLIPI clinico-genetic score,5 and together they are likely to inspire a move towards treatment models that specifically account for patient risk and disease biology.The use of the 23-gene expression profiling score and the m7-FLIPI to predict progression-free survival is all the more remarkable in view of the inherent biological diversity in follicular lymphoma and the need to contend with variations in BCL2 translocation status (t14;18/IgH-BCL2), the nature of subsequent disease progression (follicular lymphoma or transformed follicular lymphoma), the appreciation of spatial heterogeneity, and the diverse temporal evolutionary processes governing tumour initiation and progression.6–8 Arguably, although each predictor reliably identifies a population at increased risk of progression, whether or not these models represent the final stages of prognostic modelling is debatable as they will evolve in conjunction with changes in the treatment of follicular lymphoma, particularly if chemotherapy-free interventions prove successful.9 Indeed, Huet and colleagues show that the prognostic effect of the previously defined expression signatures of immune response 1 and 210 was lost in the PRIMA study cohort, demonstrating how the fortunes of these predictors can fluctuate with changes in treatment, even if a role for genes linked to the tumour microenvironment was maintained.
Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized ...that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas.
•KDM5 inhibition reverts the effects of KMT2D mutations by increasing levels of H3K4me3 and restoring expression of KMT2D-regulated genes.
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