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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-06-1800.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3188-3197
NEOPLASIA
A model of APL with FLT3 mutation is responsive to retinoic acid
and a receptor tyrosine kinase inhibitor, SU11657
Jastinder Sohal,
Vernon T. Phan,
Philip V. Chan,
Elizabeth M. Davis,
Bhumi Patel,
Louise M. Kelly,
Tinya J. Abrams,
Anne Marie O'Farrell,
D. Gary Gilliland,
Michelle M. Le
Beau, and
Scott C. Kogan
From the Comprehensive Cancer Center and the
Department of Laboratory Medicine, University of California, San
Francisco; Section of Hematology/Oncology, University of Chicago, IL;
Division of Hematology/Oncology, Brigham and Women's Hospital and
Howard Hughes Medical Institute, Harvard Medical School, Boston, MA;
and Sugen Inc, South San Francisco, CA.
The PML-RAR fusion protein is central to the pathogenesis of
acute promyelocytic leukemia (APL). Expression of this protein in
transgenic mice initiates myeloid leukemias with features of human APL,
but only after a long latency (8.5 months in MRP8 PML-RARA mice). Thus, additional changes contribute to leukemic transformation. Activating mutations of the FLT3 receptor tyrosine kinase are common in
human acute myeloid leukemias and are frequent in human APL. To assess
how activating mutations of FLT3 contribute to APL pathogenesis and
impact therapy, we used retroviral transduction to introduce an
activated allele of FLT3 into control and MRP8 PML-RARA transgenic bone marrow. Activated FLT3 cooperated with PML-RAR to induce leukemias in 62 to 299 days (median latency, 105 days). In contrast to the leukemias that arose spontaneously in
MRP8 PML-RARA mice, the activated FLT3/PML-RAR leukemias
were characterized by leukocytosis, similar to human APL with FLT3 mutations. Cytogenetic analysis revealed clonal karyotypic
abnormalities, which may contribute to pathogenesis or progression.
SU11657, a selective, oral, multitargeted tyrosine kinase inhibitor
that targets FLT3, cooperated with all-trans retinoic acid
to rapidly cause regression of leukemia. Our results suggest that the
acquisition of FLT3 mutations by cells with a pre-existing t(15;17) is
a frequent pathway to the development of APL. Our findings also
indicate that APL patients with FLT3 mutations may benefit from
combination therapy with all-trans retinoic acid plus an
FLT3 inhibitor.
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