Targeting inhibitory phosphatase signaling in high-risk childhood ALL

About 25% of childhood B cell lineage acute lymphoblastic leukemias (ALL) carry oncogenic tyrosine kinases (e.g. JAK2/CRLF2, BCR-ABL and FLT3). Tyrosine kinase driven ALL (TKD-ALL) collectively define the group of patients with the highest risk and a high frequency of drug-resistance and relapse in children.

Unlike many other leukemia types, TKD-ALL is driven by a very strong oncogene signaling molecule. In preliminary studies for this proposal, we have found that TKD-ALL differs from other leukemia subtypes in that  KD-ALL cells require inhibitory signaling molecules to counterbalance excessive signaling from the leukemia-inducing oncogene. Current therapy approaches are focused on inhibition of oncogene signaling, which induces leukemia cell death because the remaining oncogene signal is too weak to keep the leukemia cells alive.

Here we propose that pharmacological blockade of inhibitory signals will also lead to leukemia cell death, owing to excessive oncogene signaling. Indeed our preliminary data show that if oncogene signaling is increased above a certain threshold, the leukemia cells die because of extensive oxidative stress. Normal cells lacking the leukemia-inducing oncogene are spared because they are less dependent on inhibitory signaling molecules to counterbalance. Our proposal will systematically test that leukemia cells can only thrive within a certain "comfort zone" of signaling strength. Both attenuation below and exaggeration above this "comfort zone" of signal strength results in cell death. If validated, the approach of signal exaggeration will lead to the discovery and development of multiple new targets for therapy and will significantly broaden currently available treatment options for TKD-ALL.