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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2003-01-0155.
Submitted January 17, 2003
Accepted March 23, 2003
Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice identify cooperating events and genetic pathways to acute promyelocytic leukemia
Michelle M Le Beau*, Elizabeth M Davis, Bhumi Patel, Vernon T Phan, Jastinder Sohal, and Scott C Kogan
Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
Department of Laboratory Medicine, University of California, San Francisco, CA, USA
* Corresponding author; email: mlebeau{at}medicine.bsd.uchicago.edu.
Acute promyelocytic leukemia (APL) is characterized by the PML-RARA fusion gene. To identify genetic changes that cooperate with PML-RARA, we performed spectral karyotyping analysis of myeloid leukemias from transgenic PML-RARA mice, and from mice coexpressing PML-RARA and BCL2, IL3, activated IL3R, or activated FLT3. A cooperating mutation that enhanced survival (BCL2) was not sufficient to complete transformation, and was associated with multiple numerical abnormalities, whereas cooperating mutations that deregulated growth and enhanced survival were associated with normal karyotypes (IL3) or simple karyotypic changes (IL3R, FLT3). Recurring abnormalities included trisomy 15 (49%), trisomy 8 (46%), and -X/-Y (54%). The most common secondary abnormality in human APL is +8 or partial trisomy of 8q24, syntenic to mouse 15. These murine leukemias have a defined spectrum of changes that recapitulates, in part, the cytogenetic abnormalities found in human APL. Our results demonstrate that different cooperating events may generate leukemia via different pathways.
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