NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR-ABL-positive mice.

Although BCR-ABL+ stem cells in chronic myeloid leukemia (CML) resist elimination by targeted pharmacotherapy in most patients, immunological graft-versus-leukemia effects can cure the disease. Besides cytotoxic T cells, natural killer (NK) cells may have a role in immune control of CML. Here, we explored the functionality of NK cells in CML patients and in a transgenic inducible BCR-ABL mouse model. Compared with controls, NK-cell proportions among lymphocytes were decreased at diagnosis of CML and did not recover during imatinib-induced remission for 10-34 months. Functional experiments revealed limited in vitro expansion of NK cells from CML patients and a reduced degranulation response to K562 target cells both at diagnosis and during imatinib therapy. Consistent with the results in human CML, relative numbers of NK1.1+ NK cells were reduced following induction of BCR-ABL expression in mice, and the defects persisted after BCR-ABL reversion. Moreover, target-induced degranulation by expanded BCR-ABL+ NK cells was compromised. We conclude that CML is associated with quantitative and functional defects within the NK-cell compartment, which is reproduced by induced BCR-ABL expression in mice. Further work will aim at identifying the mechanisms of NK-cell deficiency in CML and at developing strategies to exploit NK cells for immunotherapy.

Leukemic spleen cells are more potent than bone marrow-derived cells in a transgenic mouse model of CML.

Spleen size ranks among the most important risk factors in chronic myeloid leukemia (CML), but the pathogenic mechanisms of splenic hematopoiesis in CML remain poorly defined. Here, we studied the biology of Bcr-Abl positive leukemia-initiating cells in the spleen, using an inducible transgenic mouse model of CML. Disease kinetics showed greater increases of immature leukemic cells in spleen vs bone marrow (BM). To assess how Bcr-Abl alters the behavior of spleen-derived CML cells, we transplanted these cells either before ('pre-uninduced') or 44 days after ('pre-induced') expression of the oncogene. Mice transplanted with pre-induced spleen cells showed significantly increased neutrophilia and splenomegaly compared with mice receiving pre-uninduced spleen cells, suggesting that Bcr-Abl expression in the donors had increased splenic tumor burden. However, pre-induction also altered the biology of these cells, as shown by a striking increase in erythropoietic potential. These results differ from those of BM-derived CML stem cells where pre-induction of Bcr-Abl had previously been shown to decrease disease transplantability. Moreover, splenic cells were less sensitive to imatinib than BM cells. In conclusion, Bcr-Abl alters the biology of splenic leukemic stem cells by a cell-autonomous mechanism, but the disease phenotype is also influenced by the microenvironment of these cells.