Interleukin 3 and granulocyte-macrophage colony-stimulating factor are notrequired for induction of chronic myeloid leukemia-like myeloproliferativedisease in mice by BCR/ABL

Primitive hematopoietic progenitors from some patients with Philadelphia ch romosome (Ph)-positive chronic myeloid leukemia (CML) express aberrant tran scripts for interleukin 3 (IL-3) and granulocyte colony-stimulating factor( G-CSF), and exhibit autonomous proliferation in serum-free cultures that is inhibited by anti-IL-3 and anti-IL-3 receptor antibodies. Expression of th e product of the Ph chromosome, the BCR/ABL oncogene, in mice by retroviral bone marrow transduction and transplantation induces CML-like leukemia, an d some leukemic mice have increased circulating IL-3, and perhaps granulocy te-macrophage colony-stimulating factor (GM-CSF), These observations raise the possibility of autocrine or paracrine cytokine production in the pathog enesis of human CML. Mice with homozygous inactivation of the II-3 gene, th e Gm-csf gene, or both, were used to test the requirement for these cytokin es for induction of CML-like disease by BCR/ ABL. Neither IL-3 nor GM-CSF w as required in donor, recipient, or both for induction of CML-like leukemia by p210 BCR/ABL. Use of novel mice deficient in both IL-3 and GM-CSF demon strated that the lack of effect on leukemogenesis was not due to redundancy between these hematopoietic growth factors. Analysis of cytokine levels in leukemic mice where either donor or recipient was II-3(-/-) indicated that the increased IL-3 originated from the recipient, suggestive of a host rea ction to the disease. These results demonstrate that IL-3 and GM-CSF are no t required for BCR/ABL-induced CML-like leukemia in mice and suggest that a utocrine production of IL-3 does not play a role in established chronic pha se CML in humans. (Blood, 2001;97:1442-1450) (C) 2001 by The American Socie ty of Hematology.