Synthetic Modeling Reveals HOXB Genes are Critical for the Initiation and Maintenance of Human Leukemia
This week we profile a recent publication in Nature Communications from
the laboratory of Dr. Andrew Weng (pictured) at BC Cancer.
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 (T-ALL) 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 (DLBCL).
What is the significance of the findings in this publication?
In this manuscript we describe a completely synthetic, efficient, and highly reproducible means for generating human T-ALL de novo from normal cord blood progenitors. We show that these synthetic leukemias appear indistinguishable from tumors arising spontaneously in human patients and undergo clonal evolution in vivo with acquisition of secondary mutations that are seen recurrently in natural leukemias. Further, we utilized this genetically defined system to reveal a role for HOXB gene activation in the earliest stages of cellular transformation which are uniquely accessible in this model during the in vitro growth phase prior to transplantation in vivo.
Modeling of human cancer using genetically engineered mouse cells has revealed many important principles of cancer biology; however, this approach is by definition problematic in that it encumbers researchers with the additional burden of having to redo experiments to ascertain which findings are actually operative in human cells. Our approach here in modeling human cancer using human cells, though simple in concept, is just now technically feasible and represents in our opinion the next logical step towards improving the way we study cancer.
The synthetic approach also holds several advantages over patient-derived xenograft (PDX) models which comprise a wide assortment of genetic variants (including abundant, often confounding passenger mutations) and are logistically difficult to generate and share. Importantly, we show that 6 of 7 gene combinations representing the major genetic classes in human T-ALL yield enhanced cell growth in vitro, demonstrating the value of this system as a general approach to modeling human leukemogenesis. Additionally, since even PDX tumors continue to evolve during serial propagation in vivo, synthetic tumors represent perhaps the only means by which we can explore early events in cellular transformation and segregate their biology from confounding effects of multiple and varied secondary events that accumulate in highly “evolved” samples.
Finally, besides its utility as a tool for discovery of basic mechanisms of human cell transformation and leukemogenesis, synthetic modeling offers a genetically defined, yet highly customizable platform that may also prove useful for targeted drug screening/validation efforts and functional testing of patient-specific genetic variants.
What are the next steps for this research?
Our next steps are to use this synthetic/engineered leukemia model to explore questions ranging from dissecting the contribution of individual genes to the leukemogenic process, defining critical waypoints during normal differentiation that are permissive or restrictive to leukemogenic transformation and the epigenetic modifiers that define them, and cytokine/growth factor/stromal interactions that support, impede, or alter the physiology of cells undergoing the earliest steps of malignant transformation. Now that tools for modifying/editing the human genome are commonplace, we feel that synthetic modeling of cancer using human cells is a promising new avenue that allows us to move beyond the limitations of human cell lines and mouse tumors, and further to specify with much greater ease the cellular, developmental, and genetic context against which we study the function of individual genetic variants and the roles they play in cancer initiation and progression.
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 BCCA and which includes Drs. Aly Karsan, Connie Eaves, Florian Kuchenbauer, and newly recruited Ly Vu whose work focuses on myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) and have developed similarly exciting synthetic AML models.
This work was funded by:
This work was funded initially 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 at BCCA, Martin Hirst at UBC, Aly Karsan in the Genome Sciences Centre at BCCA, and Raewyn Brody in the Leukemia/BMT program at VGH. My postdoctoral fellow, Manabu Kusakabe, who is first author on the manuscript also received his own funding from the Japan Society for the Promotion of Science. Our efforts were also supported by infrastructure awards from the BC Cancer Foundation.