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Hematopoietic Malignancies Demonstrate Loss-of-Function Mutations of
BAX
Jules P.P. Meijerink,
Ewald J.B.M. Mensink,
Kun Wang,
Thomas W. Sedlak,
Annet W. Slöetjes,
Theo de Witte,
Gabriel Waksman, and
Stanley J. Korsmeyer
From the Department of Hematology, University Hospital "St.
Radboud" Nijmegen, Nijmegen, the Netherlands; the Division of
Molecular Oncology, Howard Hughes Medical Institute, and the Department
of Biochemistry and Molecular Biophysics, Washington University School
of Medicine, St Louis, MO.
The BCL-2 gene family regulates the susceptibility to
apoptotic cell death in many cell types during embryonic development and normal tissue homeostasis. Deregulated expression of anti-apoptotic BCL-2 can be a primary aberration that promotes malignancy and also
confers resistance to chemotherapeutic agents. Recently, studies of
Bax-deficient mice have indicated that the pro-apoptotic BAX
molecule can function as a tumor suppressor. Consequently, we examined
human hematopoietic malignancies and found that approximately 21% of
lines possessed mutations in BAX, perhaps most commonly in the
acute lymphoblastic leukemia subset. Approximately half were nucleotide
insertions or deletions within a deoxyguanosine (G8) tract, resulting
in a proximal frame shift and loss of immunodetectable BAX protein.
Other BAX mutants bore single amino acid substitutions within
BH1 or BH3 domains, demonstrated altered patterns of protein dimerization, and had lost death-promoting activity. Thus, mutations in
the pro-apoptotic molecule BAX that confer resistance to apoptosis are
also found in malignancies.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2991-2997
© 1998 by The American Society of Hematology.
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