Targeting B-cell malignancies with poor prognosis

Using a novel functional screen, we identified CRLF2, a type I cytokine receptor also known as TSLPR, as an oncoprotein in precursor B-cell acute lymphoblastic leukemia (B-ALL).

We and others demonstrated that CRLF2 is overexpressed in ~15% of adult and high-risk pediatric B-ALL that lack rearrangements of TEL, MLL, TCF3, and BCR/ABL, and 60% of B-ALL in children with Down syndrome.

We have built on these studies by defining a relationship between Down Syndrome and B-ALL, and by demonstrating that type II JAK2 inhibitors are highly effective in models of this type of leukemia. We recently showed that HSP90 inhibitors have broad in vivo activity against mantle cell and other lymphomas, which led to clinical trials of the inhibitor AT13387.

Finally, we have trials in development targeting BCR-ABL-rearranged ALL and double-hit lymphomas using novel strategies to overcome known mechanisms of resistance.