title: Resistance to imatinib of bcr/abl p190 lymphoblastic leukemia cells.
abstract: Around 20% of patients with acute lymphoblastic leukemia are Philadelphia chromosome positive (Ph-positive acute lymphoblastic leukemia) and express the Bcr/Abl tyrosine kinase. Treatment with the tyrosine kinase inhibitor Imatinib is currently standard for chronic myelogenous leukemia, which is also caused by Bcr/Abl. However, Imatinib has shown limited efficacy for treating Ph-positive acute lymphoblastic leukemia. In our study, we have investigated the effect of Imatinib therapy on murine P190 Bcr/Abl lymphoblastic leukemia cells. Three of four cultures were very sensitive to treatment with 5 mumol/L Imatinib. Significant cell death also initially occurred when the same cultures were treated in the presence of stromal support. However, after 6 days, remaining cells started to proliferate vigorously. The Bcr/Abl tyrosine kinase present in the cells that were now able to multiply in the presence of 5 mumol/L Imatinib was still inhibited by the drug. In concordance with this, the Abl ATP-binding pocket domain of Bcr/Abl in the resistant cells did not contain point mutations which would make the protein Imatinib resistant. The effect of stroma in selecting Imatinib-resistant lymphoblasts did not require direct cell-cell contact. SDF-1alpha could substitute for the presence of stromal cells. Our results show that stroma selects Imatinib-resistant Bcr/Abl P190 lymphoblasts that are less dependent on Bcr/Abl tyrosine kinase activity. Therefore, therapy for Ph-positive acute lymphoblastic leukemia, aimed at interfering with the protective effect of stroma in combination with Imatinib, could be of benefit for the eradication of the leukemic cells.
authors.affiliation: Division of Hematology/Oncology, Section of Molecular Carcinogenesis, Childrens Hospital of Los Angeles Research Institute, Los Angeles, California 90027, USA.
authors.forename: Suparna
authors.initials: S
authors.lastname: Mishra
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Jess M
authors.initials: JM
authors.lastname: Cunnick
authors.forename: Nora
authors.initials: N
authors.lastname: Heisterkamp
authors.forename: John
authors.initials: J
authors.lastname: Groffen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D017154:Stromal Cells / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl