Despite decades of effort, the tumor genome remains ripe for discovery. The laboratory utilizes targeted deep-sequencing and functional screens 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 leukemias (ALLs). We subsequently identified somatic mutations within CRLF2 and the kinase JAK2, suggesting that agents targeting JAK2 activity will be effective for patients with ALL dependent on CRLF2. More recently, we have utilized in vitro and in vivo models of CRLF2-dependent signaling to demonstrate that inhibitors of HSP90, which promote the degradation of JAK2, have potent activity against CRFL2-rearranged leukemias. These studies have led to a clinical trial of HSP90 inhibition for patients with relapsed and refractory ALL.
CRLF2 rearrangements are the most common cytogenetic alteration in ALL among children with Down Syndrome, suggesting a biologic link between trisomy 21 and CRLF2. We have established mouse models of B-cell restriced CRLF2 expression and are using these in conjunction with models of Down Syndrome to investigate the mechanisms underlying this assocation.
In another 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. The initial efforts were the first to distinguish early and late mutations in paired lymphomas that developed in a bone marrow transplant donor and recipient several years after transplantation.