Elisa Oricchio

Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia

MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the miR-17–92 cluster, containing six individual miRNAs, is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo. Clinical use of these findings hinges on isolating the oncogenic activity within the 17–92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1-induced T-cell acute lymphoblastic leukaemia (T-ALL) in vivo. In concord with the pathogenic importance of this interaction in T-ALL, we report a novel translocation that targets the 17–92 cluster and coincides with a second rearrangement that activates Notch1. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short hairpin RNA screen for genes whose knockdown can phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and include Bim (Bcl2L11), AMP-activated kinase (Prkaa1) and the phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clampdown on several regulators of phosphatidylinositol-3-OH kinase-related survival signals by the leukaemogenic miR-19.

The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma

Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential.

Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy

CDK4 activation/RB phosphorylation occurs in 50% of indolent but high-risk follicular lymphomas and implies susceptibility to dual CDK4 and BCL2 inhibition.

Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies

Cancer evolves through the emergence and selection of molecular alterations. Cancer genome profiling has revealed that specific events are more or less likely to be co-selected, suggesting that the selection of one event depends on the others. However, the nature of these evolutionary dependencies and their impact remain unclear. Here, we designed SELECT, an algorithmic approach to systematically identify evolutionary dependencies from alteration patterns. By analyzing 6,456 genomes from multiple tumor types, we constructed a map of oncogenic dependencies associated with cellular pathways, transcriptional readouts, and therapeutic response. Finally, modeling of cancer evolution shows that alteration dependencies emerge only under conditional selection. These results provide a framework for the design of strategies to predict cancer progression and therapeutic response.

Mining the cancer genome uncovers therapeutic activity of EphA7 against lymphoma

The functional annotation of the cancer genome can reveal new opportunities for cancer therapies. The wealth of genomic data on various cancers has not yet been mined for clinically and therapeutically useful information. We use cross-comparisons of genomic data with the results of unbiased genetic screens to prioritize genomic changes for further study. In this manner, we have identified a soluble variant of the ephrin receptor A7 (EPHA7TR) as a tumor suppressor that is lost in lymphoma. We also developed antibody-based delivery to restore this tumor suppressor to the cancer cells in situ. We will discuss our strategy of screening genomic data, specific findings concerning EPHA7 and the potential for future discoveries.

Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma

SESTRIN1 is a tumor suppressor deleted or epigenetically silenced by mutated EZH2. Lymphoma’s loss is a therapeutic gain Follicular lymphoma is a relatively common and difficult-to-treat hematologic malignancy, for which no specific targeted therapy is available. Knowing that deletions of chromosome 6q are common in this tumor type, Oricchio et al. examined the genes on this chromosome and identified SESTRIN1 as a likely tumor suppressor. The authors examined the mechanism by which the loss of SESTRIN1 contributes to tumorigenesis and identified a mechanistic connection between SESTRIN1 and EZH2, an epigenetic modifier that plays a role in multiple cancer types. The authors demonstrated that the effectiveness of targeting EZH2 depends on SESTRIN1 genetic and epigenetic status and also reported that mutations in EZH2 itself can sensitize cancer cells to additional targeted therapies. Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(14;18), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as EZH2. Using a focused genetic screen, we identified SESTRIN1 as a relevant target of the 6q deletion and demonstrate tumor suppression by SESTRIN1 in vivo. Moreover, SESTRIN1 is a direct target of the lymphoma-specific EZH2 gain-of-function mutation (EZH2Y641X). SESTRIN1 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. SESTRIN1 loss represents an alternative to RRAGC mutations that maintain mTORC1 activity under nutrient starvation. The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma. Conversely, EZH2Y641X mutant lymphomas show increased sensitivity to RapaLink-1, a bifunctional mTOR inhibitor. Hence, SESTRIN1 contributes to the genetic and epigenetic control of mTORC1 in lymphoma and influences responses to targeted therapies.

Mouse models of cancer as biological filters for complex genomic data

Genetically and pathologically accurate mouse models of leukemia and lymphoma have been developed in recent years. Adoptive transfer of genetically modified hematopoietic progenitor cells enables rapid and highly controlled gain- and loss-of-function studies for these types of cancer. In this Commentary, we discuss how these highly versatile experimental approaches can be used as biological filters to pinpoint transformation-relevant activities from complex cancer genome data. We anticipate that the functional identification of genetic ‘drivers’ using mouse models of leukemia and lymphoma will facilitate the development of molecular diagnostics and mechanism-based therapies for patients that suffer from these diseases.

A cell engineering strategy to enhance the safety of stem cell therapies.

The long-term risk of malignancy associated with stem cell therapies is a significant concern in the clinical application of this exciting technology. We report a cancer-selective strategy to enhance the safety of stem cell therapies. Briefly, using a cell engineering approach, we show that aggressive cancers derived from human or murine induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) are strikingly sensitive to temporary MYC blockade. On the other hand, differentiated tissues derived from human or mouse iPSCs can readily tolerate temporary MYC inactivation. In cancer cells, endogenous MYC is required to maintain the metabolic and epigenetic functions of the embryonic and cancer-specific pyruvate kinase M2 isoform (PKM2). In summary, our results implicate PKM2 in cancers increased MYC dependence and indicate dominant MYC inhibition as a cancer-selective fail-safe for stem cell therapies.

Functional genomics lead to new therapies in follicular lymphoma

Recent technological advances allow analysis of genomic changes in cancer in unprecedented detail. The next challenge is to prioritize the multitude of genetic aberrations found and identify therapeutic opportunities. We recently completed a study that illustrates the use of unbiased genetic screens and murine cancer models to find therapeutic targets among complex genomic data. We genetically dissected the common deletion of chromosome 6q and identified the ephrin receptor A7 (EPHA7) as a tumor suppressor in lymphoma. Notably, EPHA7 encodes a soluble splice variant that acts as an extrinsic tumor suppressor. Accordingly, we developed an antibody‐based strategy to specifically deliver EPHA7 back to tumors that have lost this gene. Recent sequencing studies have implicated EPHA7 in lung cancer and other tumors, suggesting a broader therapeutic potential for antibody‐mediated delivery of this tumor suppressor for cancer therapy. Together, our comprehensive approach provides new insights into cancer biology and may directly lead to the development of new cancer therapies.

Progress Against Follicular Lymphoma

Purpose of reviewTo share the recent progress in research and new therapies against follicular lymphoma and highlight the exciting opportunities to improve the treatment of follicular lymphoma. Recent findingsFollicular lymphoma has been somewhat neglected by the research community, but recent genomic studies have identified key genetic lesions in follicular lymphoma. In addition, a new murine model is available to explore the function of these lesions in the development, progression, and treatment of follicular lymphoma. Moreover, new small-molecule inhibitors are now available that target key pathways in follicular lymphoma including B-cell receptor signaling and histone modifiers. SummaryFollicular lymphoma is a very common and still incurable form of lymphoma. However, recent genomic and in-vivo biological studies are beginning to unveil the molecular drivers of follicular lymphoma. This coincides with the development of effective small-molecule inhibitors against key targets. Together these developments suggest that we are at a long overdue watershed moment in the treatment of follicular lymphoma.