Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice parallel human acute promyelocytic leukemia.
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.
Le Beau
Michelle M
MM
Section of Hematology/Oncology, University of Chicago, Illinois 60637, USA. mlebeau@medicine.bsd.uchicago.edu
Bitts
Sheila
S
Davis
Elizabeth M
EM
Kogan
Scott C
SC
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002869:Chromosome Aberrations; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D002898:Chromosomes, Human, Pair 8; D006801:Humans; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012008:Recurrence
D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein