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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2985-2991
NEOPLASIA
Recurring chromosomal abnormalities in leukemia in
PML-RARA transgenic mice parallel human acute
promyelocytic leukemia
Michelle M. Le Beau,
Sheila Bitts,
Elizabeth M. Davis, and
Scott C. Kogan
From the Section of Hematology/Oncology, University of
Chicago, Illinois, and Department of Laboratory Medicine, University of
California, San Francisco.
Acute promyelocytic leukemia (APL) is characterized by the
t(15;17)(q22;q11.2), which results in the PML-RARA fusion
gene. In previous studies, we demonstrated that expression of a
human PML-RARA complementary DNA in murine granulocyte
precursor cells initiated the development of leukemia. However,
leukemogenesis by PML-RARA required additional genetic alterations. To
identify genetic changes that cooperate with PML-RARA in
leukemogenesis, we performed spectral karyotyping analysis of myeloid
leukemias from hMRP8-PML-RARA mice (11 cases) and from
mice coexpressing PML-RARA and BCL2 (8 cases). Clonal abnormalities were detected in 18 of 19 cases (95%).
Recurring numerical abnormalities identified in these murine leukemias
included +15 (15 cases, 79%); loss of a sex chromosome (12 cases,
63%); +8 (10 cases, 53%); +10 (9 cases, 47%); +4, +7, or +14 (8 cases each, 42%); +16 (7 cases, 37%); and +6 (5 cases, 26%). In a
series of 965 patients with APL, we identified secondary abnormalities
in 368 (38%). The most common recurring abnormalities were +8 or
partial trisomy of 8q (120 patients, 12.4%) and ider(17)
t(15;17) (42 patients, 4.4%). The critical consequence of +8 in human
leukemias appears to be the gain of 8q24, which is syntenic to mouse
15. Thus, our results suggest that PML-RARA-initiated murine leukemia
is associated with a defined spectrum of genetic changes, and that
these secondary mutations recapitulate, in part, the cytogenetic
abnormalities found in human APL.
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