HMGCLL1 is a predictive biomarker for deep molecular response to imatinib therapy in chronic myeloid leukemia View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-12-16

AUTHORS

Jong-Ho Park, Young Min Woo, Emilia Moonkyung Youm, Nada Hamad, Hong-Hee Won, Kazuhito Naka, Eun-Ju Park, June-Hee Park, Hee-Jin Kim, Sun-Hee Kim, Hyeoung-Joon Kim, Jae Sook Ahn, Sang Kyun Sohn, Joon Ho Moon, Chul Won Jung, Silvia Park, Jeffrey H. Lipton, Shinya Kimura, Jong-Won Kim, Dennis Kim

ABSTRACT

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. More... »

PAGES

1-12

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41375-018-0321-8

DOI

http://dx.doi.org/10.1038/s41375-018-0321-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1110685461

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30555164


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