Cytokine Signaling in the Abl-Induced Transformation

Rothman, Paul

Abstract

We have previously shown that murine pre-B cells transformed with the Abelson murine leukemia virus (A-MuLV) exhibit constitutive, ligand independent activation of the IL-4 and IL-7, namely Stat5 and Stat6. The constitutive activation of IL-4 and IL-7 signaling pathways has been observed in all pre-B cell lines transformed with the v-Abl oncoprotein. Using cells which contain a temperature sensitive mutant of vAbl is required for the constitutive cytokines signaling in these cells. Because IL-7 is an essential growth factor for pre-B cells and IL-4 is a growth factor for many cells, we hypothesize that the ability of v-abl to activate these signaling pathways is related to its ability to transform pre-B cells. Our initial characterization of A-MuLV-transformed pre-B cells revealed that, in these cells, v-Abl can be immunoprecipitated with the Jak1 kinase. Our recent results, using recombinant proteins, have shown that v-Abl directly associates with Jak1. In addition, the ability of v-abl to activate transcription initiation from STAT reporter constructs is repressed by expression of a dominant negative mutant of Jak1. The result leads us to hypothesize that the interaction between the v-Abl and Jak proteins might be important both the activation of cytokine signaling in these cells, and possibly, their transformed state. To address this question, we propose the following: 1) Analysis of the region(s) of v-Abl and the Jak kinases that interact. 2) To determine if v-Abl-Jak kinases interactions are required for transformation of pre-B cells, 3) To determine if v-abl can transform pre-B cells isolated from mice deficient of either Jak1, Jak3, Stat6, the gammaC receptors or the IL-Ralpha chain, 4) Analysis of the relationships between the ability of v-Abl to signal via JAK kinases and its ability to activate other signaling pathways, 5) Determine if patients with BCR-ABL have activated STATs in their leukemic cells.