Identification and Targeting of Self-renewal Mechanisms in Acute Lymphoblastic Leukemia

Relapsed acute lymphoblastic leukemia (ALL) is fatal in 70% of affected children and 90% of adults due to limited therapeutic options. Relapse occurs to due the inability of chemotherapy to kill leukemia propagating cells (LPCs), which have the unique ability to self-renew and can indefinitely propagate tumor growth from just a single cell. Leukemia propagating cells make up only 1 in every 105- 107 cells in human ALL and mouse models, precluding our ability to study them in an unbiased manner. While there is great interest in developing therapies to target self-renewal and eliminate leukemia propagating cells, the only gene associated with self-renewal in ALL thus far is LMO2, a transcription factor that is not easily therapeutically targeted. To identify additional pathways governing self-renewal in ALL, we used serial transplantation in zebrafish T-cell ALL model, which is molecularly similar human disease, to develop a library of aggressive and relapse-prone T-ALL that have high rates of self-renewal, with LPC frequencies of ~1 in 10 cells. RNA sequencing comparing the high-self renewal T-ALL samples to other samples with low self-renewal identified a possible self-renewal signature that included activation of the PI3K/AKT, FGFR1, EGFR, and WNT signaling pathways. We found that chemical inhibition of the AKT pathway killed leukemia propagating cells in zebrafish AKT-positive T-ALL and significantly decreased the percentage of animals developing leukemia in a relapse model. Based on these data, we hypothesize that the PI3K/AKT, FRF, EGFR, and/or WNT pathways play an important role in selfrenewal of leukemia propagating cells, and represent useful therapeutic targets in acute lymphoblastic leukemia.