Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Dec 16;5(1):e514.
doi: 10.1097/HS9.0000000000000514. eCollection 2021 Jan.

Gene Expression Profiling Predicts Sensitivity of Chronic Lymphocytic Leukemia Cells to Dasatinib

Tamara J Blätte  1   2 , Marcin M Machnicki  3 , Eliza Glodkowska-Mrowka  4 , Anna Dolnik  1   2 , Marta Karp  5 , Agnieszka Karczmarczyk  5 , Krzysztof Giannopoulos  5 , Lars Bullinger  1   2 , Tomasz Stoklosa  3
Affiliations

Gene Expression Profiling Predicts Sensitivity of Chronic Lymphocytic Leukemia Cells to Dasatinib

Tamara J Blätte et al. Hemasphere. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

LB involved in the advisory role or expert testimony from Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, and Pfizer; received Honoraria from Abbvie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, Novartis, Pfizer, Sanofi, and Seattle Genetics; and received financing of scientific research from Bayer. TS received Honoraria from Janssen. The remaining authors have indicated they have no potential conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Gene expression signatures in responders and nonresponders to dasatinib. (A), Viability of CLL cells isolated from responders (n = 7) and nonresponders (n = 9), treated with 180 nM dasatinib. Error bars represent a fraction of standard deviation in treated cells vs mean viability measurement in corresponding controls. XTT assay results are shown in the chart except for patients L and M (marked with asterisks) for whom XTT assay was inconclusive, and CellTiter-Blue assay results are shown. B–D, Hierarchical clustering of RNA sequencing data of all dasatinib-treated and dasatinib-untreated samples (B), all untreated samples only (C) and all treated samples only (D), each based on the Pearson correlation of DEGs between responders (n = 7) and nonresponders (n = 9). Heatmaps show row-/gene-wise Z scores; columns correspond to individual samples. Viability refers to the average cell viability observed in the in vitro cytotoxicity assays. Responders and nonresponders share distinct gene-expression signatures, both before and after treatment. CLL = chronic lymphocytic leukemia; DEG = differentially expressed gene; ID = patient identifier.
Figure 2.
Figure 2.
Key pathways associated with response to dasatinib. (A), Schematic overview of the pathway level gene expression differences between responders and nonresponders, and treated and untreated cells. Results are based on GSEA analyses of the MSigDB Hallmark collection: Green pathways indicate related gene sets that tended to be upregulated in the respective group (arrowhead) relative to one of the others (arrow tail). Analogously, red pathways indicate downregulated gene sets. B and C, PCs 1 and 2 from PCA of all dasatinib-treated and dasatinib-untreated samples for genes of the MSigDB hallmark collection gene sets HALLMARK_NOTCH_SIGNALING (B) and HALLMARK_DNA_REPAIR (C). Responders and nonresponders share distinct gene-expression signatures involving both pathways. GSEA = gene set enrichment analysis; MSigDB = molecular signatures database; PC = principal component; PCAs = principal component analyses.
See this image and copyright information in PMC

References

    1. Hallek M. Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol. 2019; 94:1266–1287. - PubMed
    1. Yosifov DY, Wolf C, Stilgenbauer S, et al. From biology to therapy: the CLL success story. HemaSphere. 2019; 3:e175. - PMC - PubMed
    1. Hantschel O, Rix U, Schmidt U, et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci U S A. 2007; 104:13283–13288. - PMC - PubMed
    1. Burger JA, O’Brien S. Evolution of CLL treatment - from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018; 15:510–527. - PubMed
    1. Amrein L, Hernandez TA, Ferrario C, et al. Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro. Br J Haematol. 2008; 143:698–706. - PubMed