Phosphoprotein profiling predicts response to tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients.
Tyrosine kinase inhibitors (TKIs) have dramatically improved treatment outcomes in chronic myeloid leukemia (CML), but a proportion of patients fail to achieve optimal molecular response. By using a phosphoproteomic approach, we aimed to discover aberrant signaling pathways and putative biomarkers in bone marrow samples of suboptimally responding patients, which could be used to guide treatment selection at the diagnosis. The study consisted of 20 chronic-phase CML patients (10 optimal and 10 suboptimal response patients based on 18 months European-Leukemia-Net criteria) and healthy bone marrow cells, and CML cell lines were used as controls. The phosphorylation profile of normal bone marrow cells diverged from CML patients expectedly but, interestingly, CML cell lines (such as K562) also showed marked difference with primary CML cells. Several phosphoproteins were elevated in suboptimal patients compared to optimal response group. Most prominent differences were seen in signal transducers and activators of transcription 5b, phospholipase C γ-1, proline-rich tyrosine kinase 2, Hck, and Paxillin. These phosphoproteins were also increased in three additional nonresponder patients studied, but each of them also had unique phosphorylation patterns, such as highly active HSP27 protein in one patient. In conclusion, suboptimal imatinib response is related to increased phosphorylation of several proteins at diagnosis, which might guide the selection of TKI therapy. Furthermore, the activation of additional BCR-ABL-independent pathways in nonresponder patients (such as the anti-apoptotic HSP27 pathway) may reveal novel therapy targets.
Hematology Research Unit Helsinki, Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
Sari E
SE
Jalkanen
Anna-Maria
AM
Lahesmaa-Korpinen
Caroline A
CA
Heckman
Ville
V
Rantanen
Kimmo
K
Porkka
Sampsa
S
Hautaniemi
Satu
S
Mustjoki
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides; D001853:Bone Marrow / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000145:classification / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D011743:Pyrimidines / Q000008:administration & dosage; D050799:STAT5 Transcription Factor / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D001549:Benzamides; D055551:HSP27 Heat-Shock Proteins; D010750:Phosphoproteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D000068877:Imatinib Mesylate; D011494:Protein Kinases; C498826:nilotinib