Response dynamics of pediatric patients with chronic myeloid leukemia on imatinib therapy.
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ABSTRACT:
SUBMITTER: Proschmann R
PROVIDER: S-EPMC5286951 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
Publications
Response dynamics of pediatric patients with chronic myeloid leukemia on imatinib therapy.
Proschmann Rick R Baldow Christoph C Rothe Tino T Suttorp Meinolf M Thiede Christian C Tauer Josephine T JT Müller Martin C MC Hochhaus Andreas A Roeder Ingo I Glauche Ingmar I
Haematologica 20161117 2
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Project description:Imatinib Mesylate is the drug used for targeted tyrosine kinase inhibition in the beginning of management of all Chronic Myeloid Leukemia (CML) newly diagnosed cases. However, resistance presents a considerable limit to its efficacy. Currently, it is impossible to anticipate IM resistance which makes the recognition of early flags an important treatment goal in CML. In this work we studied the connection between microRNA 30a (miR-30a) and Beclin 1 mediated autophagy and IM resistance in Egyptian CML patients. The study included newly diagnosed (group I, n = 20), imatinib responder (group II, n = 30), imatinib resistant (group III, n = 30) CML patients and a healthy demographically matched control group (group IV, n = 20). miR-30a expression was assayed by quantitative reverse transcription polymerase chain reaction. The variation in expression of miR-30a between CML cases and healthy controls was calculated using relative quantification method (2-ΔΔCT). Beclin 1 was assayed in Peripheral blood mononuclear cells by western blotting. miR-30a was over expressed and Beclin 1 was under expressed in imatinib responders compared to resistant cases median 1.21(0.55-3.02) versus median 0.65 (0.03-1.0) (p = 0.001) and median 950.0 (400.0-2410.0) versus, median 1570.0 (920.0-5430.0) (p < 0.001) respectively. Beclin 1 correlated significantly positively with miR-30a in new cases (p = 0.001) and negatively in imatinib responders (p = 0.021). Receiver Operating Curves demonstrated the performances of miR-30a and Beclin 1 to detect imatinib resistance. They showed sensitivities of 97.14% and 94.29% and specificities of 53.33% and 42.22% at the cut-off values of 1 and 940 respectively. Both miR-30a and Beclin 1 levels showed a relation with imatinib response and can therefore be put forward as valuable markers for detection of resistance and may also have promising future therapeutic implications.
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Project description:Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1 variant in a discovery set of CML patients (n?=?201) and successfully replicated it in a validation set (n?=?270). We also investigated the functional relevance of HMGCLL1 blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1 isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1 kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1 was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1 gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.
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