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Biochem Biophys Res Commun. 2018 Sep 10;503(3):1861-1867. doi: 10.1016/j.bbrc.2018.07.127. Epub 2018 Jul 26.

Direct and rapid identification of T315I-Mutated BCR-ABL expressing leukemic cells using infrared microspectroscopy.

Author information

1
SOLEIL Synchrotron, Saint Aubin, 91192, Gif sur Yvette, France.
2
INSERM UMR_S_935, Campus CNRS, Villejuif, France.
3
Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Locked Bag No 6, Newtown, NSW, 2042, Australia; Sydney Medical School, University of Sydney, 2006, NSW, Australia.
4
Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Locked Bag No 6, Newtown, NSW, 2042, Australia; Sydney Medical School, University of Sydney, 2006, NSW, Australia; Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, 2052, NSW, Australia.
5
INSERM UMR_S_935, Campus CNRS, Villejuif, France; Department of Hematology, Paris Sud Hematology Institute, AP-HP Hôpital Paul Brousse, Villejuif, France; INGESTEM National Pluripotent Stem Cell Infrastructure, University Paris Sud 11, Villejuif, France.
6
INSERM UMR_S_935, Campus CNRS, Villejuif, France; Department of Hematology, Paris Sud Hematology Institute, AP-HP Hôpital Paul Brousse, Villejuif, France; INGESTEM National Pluripotent Stem Cell Infrastructure, University Paris Sud 11, Villejuif, France. Electronic address: turviv33@gmail.com.

Abstract

Despite the major success obtained by the use of tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), resistances to therapies occur due to mutations in the ABL-kinase domain of the BCR-ABL oncogene. Amongst these mutations, the "gatekeeper" T315I is a major concern as it renders leukemic cells resistant to all licenced TKI except Ponatinib. We report here that Fourier transform infrared (FTIR) microspectroscopy is a powerful methodology allowing rapid and direct identification of a spectral signature in single cells expressing T315I-mutated BCR-ABL. The specificity of this spectral signature is confirmed using a Dox-inducible T315I-mutated BCR-ABL-expressing human UT-7 cells as well as in murine embryonic stem cells. Transcriptome analysis of UT-7 cells expressing BCR-ABL as compared to BCR-ABL T315I clearly identified a molecular signature which could be at the origin of the generation of metabolic changes giving rise to the spectral signature. Thus, these results suggest that this new methodology can be applied to the identification of leukemic cells harbouring the T315I mutation at the single cell level and could represent a novel early detection tool of mutant clones. It could also be applied to drug screening strategies to target T315I-mutated leukemic cells.

KEYWORDS:

BCR-ABL; CML; Infrared microspectroscopy; T315I

PMID:
30057314
DOI:
10.1016/j.bbrc.2018.07.127
[Indexed for MEDLINE]

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