Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia (original) (raw)

  1. Richard T. Williams1,
  2. Willem den Besten2,3, and
  3. Charles J. Sherr2,3,4
  4. 1 Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA;
  5. 2 Department of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA;
  6. 3 Howard Hughes Medical Institute, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

Abstract

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.

Footnotes