Subject(s)
Bone Marrow Cells/metabolism , Erythropoietin/biosynthesis , Myelodysplastic Syndromes/metabolism , Receptors, Transferrin/biosynthesis , Aged , Aged, 80 and over , Bone Marrow Cells/pathology , Erythropoietin/genetics , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Prognosis , Receptors, Transferrin/genetics , Retrospective StudiesABSTRACT
An early molecular response has a strong predictive value in chronic myeloid leukemia (CML). Recently, the halving time (velocity of early BCR-ABL1 transcript elimination) has been shown to represent an additional prognostic index. Our objective was the evaluation of the prognostic significance of the 3-month point in our population. We retrospectively collected BCR-ABL1 transcript data at different time points, events, and survival data of patients with CML treated at the Division of Hematology, San Luigi Hospital, University of Turin, Turin, Italy. Of 71 patients diagnosed from January 2005 to March 2015 in our center and treated with front-line tyrosine kinase inhibitors (imatinib, nilotinib and dasatinib), we selected those who had undergone a molecular evaluation at 3 months. The event-free survival (EFS) by the median follow-up time was the primary endpoint. The data from 50 patients with CML chronic phase were analyzed. Overall, 34 of the 50 patients (68%) had a transcript ≤ 10% at 3 months. Of those in the > 10% group, 63% had experienced an event compared with 12% in the ≤ 10% group by the median follow-up point (P < .001). The halving time threshold for discriminating between EFS was 17 days. None of the patients with a transcript > 10% at 3 months had a halving time of ≤ 17 days. Patients with BCR-ABL1 ≤ 10% and a halving time of ≤ 17 days had significantly better EFS than that of patients with BCR-ABL1 ≤ 10% and a halving time > 17 days and of patients with BCR-ABL1 > 10% (96% group 1 vs. 60% group 2 vs. 27% group 3; P < .001). Irrespective of the tyrosine kinase inhibitor used, the prognosis was significantly superior for patients with BCR-ABL1 ≤ 10% and halving time of ≤ 17 days. Our data revealed that the use of ABL1 as a control gene is reliable for the determination of the halving time in the clinical setting and highlight the importance of measuring the BCR-ABL1 transcript at CML diagnosis.
Subject(s)
Fusion Proteins, bcr-abl/genetics , Gene Expression Regulation, Leukemic/drug effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Adult , Aged , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Female , Follow-Up Studies , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Male , Middle Aged , Neoplasm Staging , Prognosis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Retrospective Studies , Survival Analysis , Time Factors , Treatment OutcomeABSTRACT
Tumor suppressor function can be modulated by subtle variation of expression levels, proper cellular compartmentalization and post-translational modifications, such as phosphorylation, acetylation and sumoylation. The non-genomic loss of function of tumor suppressors offers a challenging therapeutic opportunity. The reactivation of a tumor suppressor could indeed promote selective apoptosis of cancer cells without affecting normal cells. The identification of mechanisms that affect tumor suppressor functions is therefore essential. In this work, we show that BCR-ABL promotes the accumulation of the NFKBIA gene product, IκBα, in the cytosol through physical interaction and stabilization of the protein. Furthermore, BCR-ABL/IκBα complex acts as a scaffold protein favoring p53 nuclear exclusion. We therefore identify a novel BCR-ABL/IκBα/p53 network, whereby BCR-ABL functionally inactivates a key tumor suppressor.
Subject(s)
Fusion Proteins, bcr-abl/metabolism , I-kappa B Proteins/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Tumor Suppressor Protein p53/metabolism , Active Transport, Cell Nucleus , Cytosol/metabolism , Fusion Proteins, bcr-abl/genetics , Gene Expression Regulation, Neoplastic , HEK293 Cells , HeLa Cells , Humans , I-kappa B Proteins/genetics , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Multiprotein Complexes , NF-KappaB Inhibitor alpha , Signal Transduction , Time Factors , Transfection , Tumor Suppressor Protein p53/geneticsABSTRACT
Real-time quantitative PCR (RT-qPCR) is commonly used for follow-up of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors, but its current sensitivity does not allow detection of very low BCR-ABL levels. Therefore RT-qPCR negativity is not synonymous with complete molecular response. Replicate RT-qPCR had shown increased sensitivity in tyrosine kinase inhibitor-treated patients and was, therefore, used here to evaluate whether RT-qPCR-negative post-allogeneic stem cell transplantation (SCT) patients harbor detectable disease. Samples from 12 patients were tested at 2 time points using 82 replicates of BCR-ABL RT-qPCR. One patient (38 months after SCT) had detectable transcripts at baseline and none at the follow-up test, done at a median of 107 months after SCT. This suggests cure from CML in the majority of allogeneic SCT patients who have no transcripts detectable by replicate RT-qPCR for BCR-ABL.
