John Crispino, Ph.D. Shai Izraeli, M.D.
Northwestern University Tel Aviv University

CRLF2, JAK2, and Trisomy 21 in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite the enormous progress in therapy 15 percent to 20 percent of the children are incurable and all are subjected to highly toxic chemotherapy. Hence the challenge is to identify leukemia specific genetic alterations that could be used both as biomarkers for high-risk leukemia and as targets for novel therapy. They (and others) have recently identified such a marker: aberrant expression of CRLF2 that is often associated with lymphoid type of JAK2 mutations is associated with bad prognosis, but is also amenable to therapy with novel JAK inhibitors.

Here they propose to study the mechanism of leukemia transformation by CRLF2-JAK2 of primary murine and human hematopoietic progenitors. In addition, they will study the enigmatic phenomenon of lineage specificity of mutations in JAK2, as two somatic point mutations R683S and V617F are strictly associated with lymphoid and myeloid hematopoietic malignancies.

Finally, they will investigate the utility of JAK inhibitors as a novel therapy. As the JAK pathway is of general importance in cancer this study's implication may lie beyond childhood ALL.