Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia.
BACKGROUND
Ph-positive leukemias are caused by the aberrant fusion of the BCR and ABL genes. Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor related to imatinib, which is widely used to treat chronic myelogenous leukemia. Because Ph-positive acute lymphoblastic leukemia only responds transiently to imatinib therapy, we have used mouse models to test the efficacy of nilotinib against lymphoblastic leukemia caused by the P190 form of Bcr/Abl.


RESULTS
After transplant of 10,000 highly malignant leukemic cells into compatible recipients, untreated mice succumbed to leukemia within 21 days, whereas mice treated with 75 mg/kg nilotinib survived significantly longer. We examined cells from mice that developed leukemia while under treatment for Bcr/Abl kinase domain point mutations but these were not detected. In addition, culture of such cells ex vivo showed that they were as sensitive as the parental cell line to nilotinib but that the presence of stromal support allowed resistant cells to grow out. Nilotinib also exhibited impressive anti-leukemia activity in P190 Bcr/Abl transgenic mice that had developed overt leukemia/lymphoma masses and that otherwise would have been expected to die within 7 days. Visible lymphoma masses disappeared within six days of treatment and leukemic cell numbers in peripheral blood were significantly reduced. Treated mice survived more than 30 days.


CONCLUSIONS
These results show that nilotinib has very impressive anti-leukemia activity but that lymphoblastic leukemia cells can become unresponsive to it both in vitro and in vivo through mechanisms that appear to be Bcr/Abl independent.
Kaur
Pavinder
P
Section of Molecular Carcinogenesis, Division of Hematology/Oncology, Saban Research Institute, Childrens Hospital Los Angeles and the Keck School of Medicine, University of Southern California, Los Angeles, California, USA. pavinder@gmail.com
Feldhahn
Niklas
N
Zhang
Bin
B
Trageser
Daniel
D
Müschen
Markus
M
Pertz
Veerle
V
Groffen
John
J
Heisterkamp
Nora
N
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2 / Q000187:drug effects / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011743:Pyrimidines / Q000627:therapeutic use*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2; C498826:nilotinib