Despite decades of effort, the tumor genome remains ripe for discovery. The laboratory utilizes both functional and sequencing approaches to identify and characterize oncogene alterations directly from tumor specimens. Newly-identified alterations are further assayed using a variety of in vitro and in vivo methods, with the ultimate goal of translating discoveries into novel therapies.
Our initial efforts identified CRLF2, a previously obscure cytokine receptor, as an essential oncogene in 5-10% of adult and pediatric acute lymphoblastic leukemia (ALL). We subsequently demonstrated that agents targeting HSP90 or BRD4 are active in human leukemias with CRLF2 alterations, defined the mechanisms of CRLF2 locus rearrangement and clarified mechanisms that link CRLF2 alterations with Down Syndrome. These findings have inspired clinical trials in both children and adults with this poor-risk subset of ALL.
In a second line of inquiry, we are assaying the nature and determinants of DNA repair in mammalian cells. These studies extend from tumor specimens, where we have characterized a novel oncogene-DNA repair interaction, to human embryonic and induced pluripotent cells.
Finally, our laboratory is actively investigating the molecular evolution of somatic alterations in lymphoid malignancies. We utilize ultra-deep sequencing of subpopulations sorted from bone marrow specimens to trace the ontogeny of specific alterations identified within lymphomas.