PTCH1 is a reliable marker for predicting imatinib response in chronic myeloid leukemia patients in chronic phase

Abstract

Patched homolog 1 gene (PTCH1) expression and the ratio of PTCH1 to Smoothened (SMO) expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML) patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP) using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72). In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF), which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013), probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02), and proportions of early molecular failure (14% vs. 43%, P = 0.015). Every progression to an advanced phase (n = 3) and CML-related death (n = 2) occurred in the low PTCH1 group (P<0.001 for both comparisons). PTCH1 was an independent prognostic factor for the prediction of IF. We also validated previously published thresholds for PTCH1 expression. Therefore, we confirmed that PTCH1 expression can predict the imatinib response in CML patients in CP by applying a more rigorous statistical analysis. Thus, PTCH1 expression is a promising molecular marker for predicting the imatinib response in CML patients in CP.

Study of PTCH1 Gene as a Prognostic Marker to Predict Imatinib Response in CML Patients: a Single Egyptian Center Experience

“…PTCH1 is a component of the Hedgehog (Hh) signaling pathway, which is a key regulator of cell proliferation, cell surveillance, embryonic development, adult tissue homeostasis, and stem cell quiescence (5) .…”

“…The expression of the PTCH1 gene does not appear to be linked to the dasatinib response, and its link to the nilotinib response has not been investigated. If there is no link between PTCH1 expression and nilotinib response, PTCH1 expression might be used to guide first-line TKI treatment; if low PTCH1 expression is observed at diagnosis, a second-generation TKI would be a preferable alternative (5) . The aim of our study was to assess PTCH1 gene expression and its relation to the response of adult patients with chronic myeloid leukemia to imatinib treatment.…”

Understanding the Hedgehog Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Necessary Step toward a Cure

“…As an example, Zhao et al showed that the Hh pathway controls the frequency and maintenance of CML blast crisis LSCs [ 56 ]. In addition, the importance of this signaling pathway is tangible given that PTC1 expression is useful for determining the response to the TKI, imatinib, in patients with CML [ 71 , 72 ].…”

The Levels of FoxO3a Predict the Failure of Imatinib Mesylate Therapy among Chronic Myeloid Leukemia Patients

“…The case of imatinib resistance has been reported, and the heterogeneous mechanism is proposed to underlie this resistance including BCR-ABL gene amplification and gene mutation which may lead to incomplete inhibition [6]. Previous studies had proposed some markers that might predict the treatment response of IM therapy including human organic cation transporter 1, patched homolog 1, prostaglandin-endoperoxide synthase 1, cyclooxgenase 1, and forkhead transcription factor 3a (FOXO3a) [7], [8], [9]. Of those, the role of FoxO3a had limited evidence.…”