title: BCR-ABL-transformed GMP as myeloid leukemic stem cells.
abstract: 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.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093-0820, USA.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Minami
authors.forename: Scott A
authors.initials: SA
authors.lastname: Stuart
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Ikawa
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Asoka
authors.initials: A
authors.lastname: Banno
authors.forename: Irina C
authors.initials: IC
authors.lastname: Hunton
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Young
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.forename: Cornelis
authors.initials: C
authors.lastname: Murre
authors.forename: Catriona H M
authors.initials: CH
authors.lastname: Jamieson
authors.forename: Jean Y J
authors.initials: JY
authors.lastname: Wang
mesh_terms: 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
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016044:Fusion Proteins, bcr-abl; D051176:beta Catenin; C075668:Tcf3 protein, mouse