Skip to main content
Publications of the Week

Epigenetic Restoration of Fetal-Like IGF1 Signaling Inhibits Leukemia Stem Cell Activity

By October 19, 2018October 22nd, 2018No Comments

Read the Publication

This week we profile a recent publication in Cell Stem Cell from the laboratory of
Dr. Andrew Weng (pictured, right) at the Terry Fox Laboratory.

Can you provide a brief overview of your lab’s current research focus?

My research program focuses on the pathogenesis of lymphoid malignancy and entails two major arms. First, we have explored the role of NOTCH1 and other oncogenes/tumor suppressors in the genesis and propagation of T-cell acute lymphoblastic leukemia including studies on downstream target genes/pathways and identifying mechanisms operative in leukemia stem cells. As a second and more recent focus, my lab is using state-of-the-art single cell analytic techniques (mass cytometry/CyTOF and single cell RNA-seq) to obtain highly resolved phenotypic maps of heterogeneous cell populations present in patient lymphoma biopsy samples including both malignant and reactive immune cell compartments. We are currently focusing these efforts on two large patient cohorts of follicular lymphoma and diffuse large B cell lymphoma.

What is the significance of the findings in this publication?

In this manuscript we describe a novel approach in studying cancer biology – we explored genetic/epigenetic programming in fetal tissues to reveal extinct cellular processes that, when “re-awakened” in adult tissues, alters and ultimately disrupts the function of cancer stem cells. We happened upon this idea from work by Connie Eaves and others who had previously shown that the behavior of fetal hematopoietic stem cells (HSC) was very distinct from that of adult HSC. Our initial thought was that pediatric leukemias (which typically have good clinical outcomes) might have inherited their functional programs from fetal HSC, while adult leukemias (which typically have poor clinical outcomes) may more resemble adult HSC. In this particular study, we ultimately concluded that both pediatric and adult T-cell leukemias have “adult”-type regulation of IGF signaling; however, we were still able to restore “fetal”-like IGF signaling in both pediatric and adult leukemia cells to exhaust and thus deplete their leukemia stem cells. Because we discovered that the epigenetic modifier EZH2 controlled the switch between “fetal” and “adult” programs, it suggests that EHZ2 inhibitor drugs that are currently in clinical trials could be used to specifically target leukemia stem cells in both pediatric and adult patients.

What are the next steps for this research?

We have recently developed a new “synthetic” model for studying human T-cell leukemia in which we add specific combinations of oncogenes into normal human cord blood cells. Strikingly, in a matter of weeks to months these cells look and behave like patient leukemia samples – they grow aggressively in vitro and when transplanted into mice, create disseminated leukemias that are nearly identical to human disease. So our next steps are to use the synthetic leukemia model to determine whether the fetal/adult paradigm we have discovered is operative in just the one type of leukemia we reported in the manuscript, or if it is also applicable to other types of human leukemia. Of note, while my lab focuses on T-cell leukemias, we work as team with other labs in the Leukemia and Myeloma Program (LaMP) based largely in the Terry Fox Lab at BC Cancer and which includes Drs. Aly Karsan, Keith Humphries, Connie Eaves, and newly recruited Florian Kuchenbauer whose work focuses on myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) and have developed similarly exciting synthetic AML models.

This research was funded by:

This work was funded initially by an operating grant from CIHR, and then by a program project/group grant in acute leukemia from the Terry Fox Research Institute (TFRI). Our TFRI team included my lab and those of Drs. Keith Humphries, Connie Eaves, and Peter Lansdorp in the Terry Fox Lab and Aly Karsan in the Genome Sciences Centre at BC Cancer, and Raewyn Brody in the Leukemia/BMT program at VGH. My postdoctoral fellow, Vincenzo Giambra, who is first author on the manuscript also received his own funding from the Fondazione con il SUD and Italian Association for Research on Cancer. Our efforts were also supported by infrastructure awards from the BC Cancer Foundation.

Read the Publication