BCR-ABL-transformed GMP as myeloid leukemic stem cells.
During blast crisis of chronic myelogenous leukemia (CML), abnormal granulocyte macrophage progenitors (GMP) with nuclear beta-catenin acquire self-renewal potential and may function as leukemic stem cells (Jamieson et al. N Engl J Med, 2004). To develop a mouse model for CML-initiating GMP, we expressed p210(BCR-ABL) in an established line of E2A-knockout mouse BM cells that retain pluripotency in ex vivo culture. Expression of BCR-ABL in these cells reproducibly stimulated myeloid expansion in culture and generated leukemia-initiating cells specifically in the GMP compartment. The leukemogenic GMP displayed higher levels of beta-catenin activity than either the nontransformed GMP or the transformed nonGMP, both in culture and in transplanted mouse BM. Although E2A-deficiency may have contributed to the formation of leukemogenic GMP, restoration of E2A-function did not reverse BCR-ABL-induced transformation. These results provide further evidence that BCR-ABL-transformed GMP with abnormal beta-catenin activity can function as leukemic stem cells.
Minami
Yosuke
Y
Division of Hematology-Oncology, Department of Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093-0820, USA.
Stuart
Scott A
SA
Ikawa
Tomokatsu
T
Jiang
Yong
Y
Banno
Asoka
A
Hunton
Irina C
IC
Young
Dennis J
DJ
Naoe
Tomoki
T
Murre
Cornelis
C
Jamieson
Catriona H M
CH
Wang
Jean Y J
JY
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D055014:Granulocyte-Macrophage Progenitor Cells / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D023461:Myeloid Progenitor Cells / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D016044:Fusion Proteins, bcr-abl; D051176:beta Catenin; C075668:Tcf3 protein, mouse