Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias.
Chronic myelogenous leukemia is a myeloproliferative disorder (MPD) that, over time, progresses to acute leukemia. Both processes are closely associated with the t(9;22) chromosomal translocation that creates the BCR/ABL fusion gene in hematopoietic stem cells (HSCs) and their progeny. Chronic myelogenous leukemia is therefore classified as an HSC disorder in which a clone of multipotent HSCs is likely to be malignantly transformed, although direct evidence for malignant t(9;22)+ HSCs is lacking. To test whether HSC malignancy is required, we generated hMRP8p210BCR/ABL transgenic mice in which expression of BCR/ABL is absent in HSCs and targeted exclusively to myeloid progenitors and their myelomonocytic progeny. Four of 13 BCR/ABL transgenic founders developed a chronic MPD, but only one progressed to blast crisis. To address whether additional oncogenic events are required for progression to acute disease, we crossed hMRP8p210BCR/ABL mice to apoptosis-resistant hMRP8BCL-2 mice. Of 18 double-transgenic animals, 9 developed acute myeloid leukemias that were transplantable to wild-type recipients. Taken together, these data indicate that a MPD can arise in mice without expression of BCR/ABL in HSCs and that additional mutations inhibiting programmed cell death may be critical in the transition of this disease to blast-crisis leukemia.
Jaiswal
Siddhartha
S
Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Traver
David
D
Miyamoto
Toshihiro
T
Akashi
Koichi
K
Lagasse
Eric
E
Weissman
Irving L
IL
D000818:Animals; D017209:Apoptosis; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D016313:Genes, abl; D019254:Genes, bcl-2; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000378:metabolism* / Q000473:pathology