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Gene expression signature that predicts early molecular response failure in chronic-phase CML patients on frontline imatinib.

ABSTRACT: In chronic-phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR; EMR failure: BCR-ABL1 >10% on the international scale at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (eg, Myc, β-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared with low-risk (LR-GES) patients (78% vs 5%; P < .0001), with an overall accuracy of 93%. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10%). However, HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared with LR-GES patients. This novel multigene signature may be useful for selecting patients at high risk of EMR failure on standard therapy who may benefit from trials of more potent kinase inhibitors or other experimental approaches.

SUBMITTER: Kok CH

PROVIDER: S-EPMC6538873 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Gene expression signature that predicts early molecular response failure in chronic-phase CML patients on frontline imatinib.

Kok Chung H CH Yeung David T DT Lu Liu L Watkins Dale B DB Leclercq Tamara M TM Dang Phuong P Saunders Verity A VA Reynolds John J White Deborah L DL Hughes Timothy P TP

Blood advances 20190501 10

In chronic-phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR; EMR failure: <i>BCR</i>-<i>ABL1</i> >10% on the international scale at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes t ...[more]

PMID: 31126916

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Project description:Chronic myelogenous leukaemia (CML) is a malignant disorder of the hematopoietic stem cell, which is characterized by the reciprocal translocation between chromosomes 9 and 22 (t(9;22)(q34;q11)) The translocation results in the formation of the BCR-ABL fusion oncogene encoding a protein with constitutive activated tyrosine kinase activity which plays a central role in the pathogenesis of the disease. There are still several open questions with respect to BCR-ABL-induced malignant transformation. A large limitation of the existing data about BCR-ABL effects is that they are derived to a great proportion from human hematopoietic cell lines, BCR-ABL-transformed murine cell lines or fibroblasts and mouse models, which might not be representative for chronic phase CML. A suitable cell population for studies on CML biology are primary hematopoietic stem and progenitor cells from patients with CML. Therefore, we provide in this study a genome-wide expression signature of highly enriched CD34+ cells from bone marrow (BM) of untreated patients with CML in chronic phase. Gene expression profiles of immunomagnetically enriched BM CML CD34+ cells (n=9) were compared with those of normal BM CD34+ cells (n=8) using microarrays covering 8.746 genes. Total RNA was extracted, reversely transcribed, in vitro transcribed and labelled and hybridized to Affymetrix HG Focus Arrays. Following quality control and normalization differentially expressed genes were identified by significance analysis of microarrays (SAM). Comparing both groups 918 genes were significantly differentially expressed (q value <0.1%; fold change > 1.3). Several of the BCR-ABL-induced effects described in cell lines and BCR-ABL-transduced cells could also be found in primary CML progenitor cells as for example the transcriptional activation of the classical MAPK pathway and the PI3 kinase/AKT pathway and the down-regulation of the pro-apoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34+ cells were identified. These include an up-regulation of components of the TGFb signalling pathway and the non-canonical Wnt/Ca2+ pathway, a transcriptional activation of fetal haemoglobin genes and genes associated with early hematopoietic stem cells (HSC) such as HoxA9 and MEIS1 and up-regulation of genes involved in fatty acid metabolism, of the thrombin receptor PAR1 and the neuroepithelial cell transforming gene 1. Differential expression of differentiation-associated genes suggested an alteration of the composition of the CD34+ cell population in CML. This was confirmed by immunophenotypical subset analyses of chronic phase CML CD34+ cells showing an increase of erythroid progenitors and a decrease of granulocyte-macrophage progenitor cells while the proportion of HSC was similar in normal and CML CD34+ cells. In conclusion, our results give novel insights into the biology of CML hematopoietic stem and progenitor cells and could be the basis for identification of new targets for therapy. Keywords: ordered

Project description:BackgroundTreatment of patients with chronic myeloid leukaemia (CML) has become increasingly difficult in recent years due to the variety of treatment options available and challenge deciding on the most appropriate treatment strategy for an individual patient. To facilitate the treatment strategy decision, disease assessment should involve molecular response to initial treatment for an individual patient. Patients predicted not to achieve major molecular response (MMR) at 24 months to frontline imatinib may be better treated with alternative frontline therapies, such as nilotinib or dasatinib. The aims of this study were to i) understand the clinical prediction 'rules' for predicting MMR at 24 months for CML patients treated with imatinib using clinical, molecular, and cell count observations (predictive factors collected at diagnosis and categorised based on available knowledge) and ii) develop a predictive model for CML treatment management. This predictive model was developed, based on CML patients undergoing imatinib therapy enrolled in the TIDEL II clinical trial with an experimentally identified achieving MMR group and non-achieving MMR group, by addressing the challenge as a machine learning problem. The recommended model was validated externally using an independent data set from King Faisal Specialist Hospital and Research Centre, Saudi Arabia.Principle findingsThe common prognostic scores yielded similar sensitivity performance in testing and validation datasets and are therefore good predictors of the positive group. The G-mean and F-score values in our models outperformed the common prognostic scores in testing and validation datasets and are therefore good predictors for both the positive and negative groups. Furthermore, a high PPV above 65% indicated that our models are appropriate for making decisions at diagnosis and pre-therapy. Study limitations include that prior knowledge may change based on varying expert opinions; hence, representing the category boundaries of each predictive factor could dramatically change performance of the models.

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Gene expression signature that predicts early molecular response failure in chronic-phase CML patients on frontline imatinib.

Publications

Gene expression signature that predicts early molecular response failure in chronic-phase CML patients on frontline imatinib.

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