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Blood, 1 January 2002, Vol. 99, No. 1, pp. 300-309
NEOPLASIA
Ataxia telangiectasia mutated-deficient B-cell chronic
lymphocytic leukemia occurs in pregerminal center cells and results in
defective damage response and unrepaired chromosome damage
Tatjana Stankovic,
Grant S. Stewart,
Christopher Fegan,
Paul Biggs,
James Last,
Philip J. Byrd,
Russell D. Keenan,
Paul A. H. Moss, and
Alexander M. R. Taylor
From the University of Birmingham, CRC Institute for
Cancer Studies, The Medical School, Edgbaston; and the Department of
Haematology, Birmingham Heartlands Hospital, Birmingham, United
Kingdom.
B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous
disease involving more than one molecular mechanism that leads to the
transformation of CD5+ B cells at either the pregerminal or
postgerminal center stage of differentiation. It was previously
demonstrated that ataxia telangiectasia mutated (ATM) gene
mutations can occur in B-CLL and cause a defect in the p53 pathway.
Here the role of ATM mutations in the pathogenesis of B-CLL
is addressed. Of 50 B-CLL tumors with fully analyzed
ATM and TP53, 16 had ATM mutations.
Six of 50 B-CLLs showed mutations in TP53 and the remaining
28 tumors had wild-type ATM or TP53. No tumor
had both ATM and TP53 mutations. Remarkably,
all 16 ATM mutant B-CLLs showed the absence of somatic variable region heavy chain hypermutation indicating a
pregerminal center cell origin and a common pathogenesis for
these tumors. Furthermore, in 5 of the 16 B-CLLs, ATM
mutation preceded the transformation stage of differentiation. At the
cellular level, ATM mutant tumors exhibited a deficient
ATM-dependent p53 response to gamma irradiation, failure to
up-regulate TRAIL-R2, a downstream target that links
irradiation-induced p53 response with apoptosis, and an
inability to repair induced chromosome breaks. Mantle cell lymphoma
(MCL) is also of pregerminal center origin and ATM
mutations are frequent in this malignancy. It is concluded
that ATM is likely to play an important role at the pregerminal center
stage and a model is proposed where loss of ATM function during B-cell
ontogeny drives B-CLL tumorigenesis in pregerminal B cells by a dual
defect in p53 damage response and repair of chromosome breaks.
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