Targeting Signaling in Cancer – lessons from acute lymphoblastic leukemia

Most of the novel targeted cancer therapies block signaling kinases. Here I shall discuss the opportunities and challenges as presented by kinase driven acute lymphoblastic leukemia (Herein ALL) Somatic activation of JAK/STAT signaling in B cell precursor ALL is most commonly caused by aberrant expression of CRLF2 that by heterodimerization with interleukin 7 receptor alpha (IL7R) creates the receptor to Thymic Stromal Lymphopoietin (TSLP). This receptor signals through JAK1 and JAK2. Often additional activating mutations in JAK enzymes or CRLF2 or IL7R cause constitutive activation of this pathway. These aberrations characterize 50% of the ALLs in children with Down Syndrome and 5-10% of ALLs in children and young adults without Down Syndrome. The prognosis of these leukemias is poor. I will describe our unpublished experiments demonstrating the importance of CRLF2/IL7R in generating ALL in primary human hematopoietic progenitors. Our detailed genomic studies of diagnostic and relapse CRLF2/JAK mutated ALLs demonstrate the significant therapeutic challenges posed by these leukemias. Importantly, we discovered that Ruxolitinib, the JAK1 and JAK2 inhibitor can act as a double edge sword. Low dose Ruxolitinib paradoxically enhances survival JAK driven B-ALL while high dose eliminates the leukemic cells. This observation may represent a general phenomenon of B-ALL cells that could complicate treatment with signaling inhibitors.