Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and can be separated into two subtypes based upon molecular features with similarities to germinal center B-cells (GCB-like) or activated B-cells (ABC-like). Here we identify gain of 3q27.2 as being significantly associated with adverse outcome in DLBCL and linked with the ABC-like subtype. This lesion includes the BCL6 oncogene, but does not alter BCL6 transcript levels or target-gene repression. Separately, we identify expression of BCL6 in a subset of human hematopoietic stem/progenitor cells (HSPCs). We therefore hypothesize that BCL6 may act by hit-and-run oncogenesis. We model this by transiently expressing Bcl6 within murine HSPCs, and find it causes mature B-cell lymphomas that lack Bcl6 expression and target-gene repression, are transcriptionally similar to post-GCB cells, and show epigenetic changes that are conserved from HSPCs to mature B-cells. Together these results suggest that Bcl6 may function in a hit-and-run role in lymphomagenesis.

Transgenic expression of the MafB oncogene in haematopoietic stem/progenitor cells induces plasma cell neoplasia reminiscent of human multiple myeloma and suggests DNA methylation as cause of malignant transformation.

• Crebbp inactivation perturbs B-cell development, but cooperates with Bcl2 overexpression to promote lymphoma.• Transcriptional and epigenetic signatures of Crebbp loss implicate Myc in disease etiology.CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 overexpression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B cells, we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes. However, B cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions, enriched for Myc DNA binding motifs, and showed Myc binding. Through the analysis of CREBBP mutations from a large cohort of primary human FL and DLBCL, we show a significant difference in the spectrum of CREBBP mutations in these 2 diseases, with higher frequencies of nonsense/ frameshift mutations in DLBCL compared with FL. Together, our data therefore provide important links between Crebbp inactivation and Bcl2 dependence and show a role for Crebbp inactivation in the induction of Myc expression. We suggest this may parallel the role of CREBBP frameshift/nonsense mutations in DLBCL that result in loss of the protein, but may contrast the role of missense mutations in the lysine acetyltransferase domain that are more frequently observed in FL and yield an inactive protein.

The prerequisite to prevent childhood B-cell acute lymphoblastic leukemia (B-ALL) is to decipher its etiology. The current model suggests that infection triggers B-ALL development through induction of activation-induced cytidine deaminase (AID; also known as AICDA) in precursor B-cells. This evidence has been largely acquired through the use of ex vivo functional studies. However, whether this mechanism governs native non-transplant B-ALL development is unknown. Here we show that, surprisingly, AID genetic deletion does not affect B-ALL development in Pax5-haploinsufficient mice prone to B-ALL upon natural infection exposure. We next test the effect of premature AID expression from earliest pro-B-cell stages in B-cell transformation. The generation of AID off-target mutagenic activity in precursor B-cells does not promote B-ALL. Likewise, known drivers of human B-ALL are not preferentially targeted by AID. Overall these results suggest that infections promote B-ALL through AID-independent mechanisms, providing evidence for a new model of childhood B-ALL development.

The impact of LMO2 expression on cell lineage decisions during T‐cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T‐cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human‐like T‐ALL. In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T‐ALL. The resulting T‐ALLs lacked LMO2 and its target‐gene expression, and histologically, transcriptionally, and genetically similar to human LMO2‐driven T‐ALL. We next found that during T‐ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T‐ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre‐mediated activation of Lmo2 at different stages of B‐cell development induces systematically and unexpectedly T‐ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T‐ALL to current therapies.

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Study design: Retrospective review of a National Inpatient Sample from 2000 to 2014. Key findings: Of 3487 patients with Marfan syndrome (MFS; 97%) or Ehlers-Danlos syndrome (EDS; 3%) who underwent aortic aneurysm repair, 85% were performed at teaching hospitals. Approximately 66% were thoracic, 15% thoracoabdominal, and 18% abdominal aortic aneurysms (AAAs) in each group. Open surgical repair was performed in 95% of cases and endovascular repair (primarily for AAAs) in 5% of each group. Urgent or emergent repair was performed in approximately 44% of cases in each group. Patients at nonteaching hospitals were more likely to have a dissection (49% vs 38%) (P ¼ .02). In a multivariable logistic regression model, there were no differences in perioperative mortality (5%), length of stay (8 days), or other complications between teaching and nonteaching hospitals. Of note, patients presenting with dissection were three times more likely to die than those without dissection, and the most common perioperative complication at both types of hospitals was hemorrhage in about 45% of patients.Conclusion: Although most patients with MFS and EDS who undergo aortic aneurysm repair do so at teaching hospitals, patients who undergo repair at nonteaching hospitals do not have worse mortality or morbidity despite a higher incidence of dissection.Commentary: This article is an excellent review of a large number of patients with connective tissue disorders treated for aortic aneurysms. Previous studies have shown improved outcomes when ruptured AAAs, ruptured cerebral aneurysms, and complex hepatobiliary surgery were performed at teaching hospitals as compared with nonteaching hospitals, which makes this article very provocative.Experts in surgical treatment of patients with connective tissue disorders such as MFS and EDS recommend complex open reconstruction with visceral aortic branched grafts and do not recommend repair with a visceral patch inclusion for fear of recurrent aneurysms at the patch. By anastomosing branch grafts directly to the origin of the celiac, superior mesenteric, and renal arteries, the chance of recurrent aneurysmal dilation is decreased. Patients treated with endovascular intervention have a high likelihood of requiring subsequent procedures.Take-home Message: I recommend reading the key findings in this article a couple of times, especially for vascular residents. For patients with MFS and EDS treated for aortic aneurysms, (1) MFS is a much more common etiology than EDS, (2) almost one-half required urgent intervention, (3) almost one-half suffered hemorrhagic complications after open surgery, (4) endovascular treatment is generally not recommended, and (5) open surgical repair should primarily consist of aortic branch grafting to visceral branches and the patch inclusion technique should be avoided. Despite the urgency and complexity of these operations, the perioperative mortality was only about 5% at both teaching and nonteaching hospitals. Amazing.Carotid-subclavian bypass and chimney grafts work equally...