The level of BCR-ABL1 kinase activity before treatment does not identify chronic myeloid leukemia patients who fail to achieve a complete cytogenetic response on imatinib.
Imatinib is currently the first line therapy for newly diagnosed patients with chronic myeloid leukemia. However, 20-25% of patients do not achieve durable complete cytogenetic responses. The mechanism underlying this primary resistance is unknown, but variations in BCR-ABL1 kinase activity may play a role and can be investigated by measuring the autophosphorylation levels of BCR-ABL1 or of a surrogate target such as Crkl. In this study we used flow cytometry to investigate the in vitro inhibition of Crkl phosphorylation by imatinib in CD34(+) cells in diagnostic samples from two groups of patients distinguished by their cytogenetic response. No difference in inhibition of Crkl phosphorylation was observed in the two groups. The observation that increasing the dose of imatinib in vivo did not increase the level of cytogenetic response in some non-responders suggests that in at least a proportion of patients imatinib resistance may be due to activation of BCR-ABL1-independent pathway.
Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom. jamshid.sorouri-khorashad06@imperial.ac.uk
Jamshid Sorouri
JS
Khorashad
Simon
S
Wagner
Liat
L
Greener
David
D
Marin
Alistair
A
Reid
Dragana
D
Milojkovic
Hetal
H
Patel
Shaun
S
Willimott
Katy
K
Rezvani
Gareth
G
Gerrard
Sandra
S
Loaiza
John
J
Davis
John
J
Goldman
Junia
J
Melo
Jane
J
Apperley
Letizia
L
Foroni
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides; D015704:CD4 Antigens / Q000032:analysis; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001549:Benzamides; D015704:CD4 Antigens; C082869:CRKL protein; D009687:Nuclear Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl