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Cytokine-dependent imatinib resistance in mouse BCR-ABL + , Arf -null lymphoblastic leukemia

2007; Cold Spring Harbor Laboratory Press; Volume: 21; Issue: 18 Linguagem: Inglês

10.1101/gad.1588607

1549-5477

Richard T. Williams, Willem den Besten, Charles J. Sherr,

Chronic Lymphocytic Leukemia Research

Retroviral transduction of the BCR-ABL kinase into primary mouse bone marrow cells lacking the Arf tumor suppressor rapidly generates polyclonal populations of continuously self-renewing pre-B cells, virtually all of which have leukemic potential. Intravenous infusion of 20 such cells into healthy syngeneic mice induces rapidly fatal, transplantable lymphoblastic leukemias that resist imatinib therapy. Introduction of BCR-ABL into Arf -null severe combined immunodeficient (SCID) bone marrow progenitors lacking the cytokine receptor common γ-chain yields leukemogenic pre-B cells that exhibit greater sensitivity to imatinib in vivo. Hence, salutary cytokines in the hematopoietic microenvironment can facilitate leukemic proliferation and confer resistance to targeted therapy.