p53 Deficiency Increases Transformation by v-Abl and Rescues the Ability of a C-Terminally Truncated v-Abl Mutant To Induce Pre-B Lymphoma In Vivo

Abstract

Abelson murine leukemia virus (A-MuLV) is an acute transforming retrovirus that preferentially transforms early B-lineage cells both in vivo and in vitro. Its transforming protein, v-Abl, is a tyrosine kinase related to v-Src but containing an extended C-terminal domain. Many mutations affecting the C-terminal portion of the molecule block the pre-B-transforming activity of v-Abl without affecting the fibroblast-transforming ability. In this study we have determined the abilities of both wild-type and C-terminally truncated (p90) forms of v-Abl to transform cells from p53^−/− mice. Lack of p53 increases the susceptibility of bone marrow cells to transformation by v-Abl by a factor of more than 7 but does not alter v-Abl's preference for B220⁺ IgM⁻ pre-B cells. p53-deficient mice have earlier tumor onset, more rapid tumor progression, and decreased survival time following A-MuLV infection, but all of the tumors are pre-B lymphomas. Thus, p53-dependent pathways inhibit v-Abl transformation but play no role in conferring preferential transformation of pre-B cells. Surprisingly, the C-terminally truncated form of v-Abl (p90) transforms pre-B cells very efficiently in mice lacking p53, thus demonstrating that the C terminus of v-Abl does not determine preB tropism but is necessary to overcome p53-dependent inhibition of transformation.

ACKNOWLEDGMENTS

We are grateful to members of the Calame and Goff laboratories for helpful discussions and to Cristina Angelin-Duclos for critically reading the manuscript. We thank Sharon Boast and Yuming Xu for expert technical assistance.

This work was supported by grant PO1 CA75339 to both S.P.G. and K.C. S.P.G. is an investigator of the Howard Hughes Medical Institute.