Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells
Aditi Shastri, … , Britta Will, Amit Verma
Aditi Shastri, … , Britta Will, Amit Verma
Published September 25, 2018
Citation Information: J Clin Invest. 2018;128(12):5479-5488. https://doi.org/10.1172/JCI120156.
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Research Article Hematology

Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells

Abstract

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Transcriptomic analysis of stem and progenitor populations in MDS and AML demonstrated overexpression of STAT3 that was validated in an independent cohort. STAT3 overexpression was predictive of a shorter survival and worse clinical features in a large MDS cohort. High STAT3 expression signature in MDS CD34+ cells was similar to known preleukemic gene signatures. Functionally, STAT3 inhibition by a clinical, antisense oligonucleotide, AZD9150, led to reduced viability and increased apoptosis in leukemic cell lines. AZD9150 was rapidly incorporated by primary MDS/AML stem and progenitor cells and led to increased hematopoietic differentiation. STAT3 knockdown also impaired leukemic growth in vivo and led to decreased expression of MCL1 and other oncogenic genes in malignant cells. These studies demonstrate that STAT3 is an adverse prognostic factor in MDS/AML and provide a preclinical rationale for studies using AZD9150 in these diseases.

Authors

Aditi Shastri, Gaurav Choudhary, Margarida Teixeira, Shanisha Gordon-Mitchell, Nandini Ramachandra, Lumie Bernard, Sanchari Bhattacharyya, Robert Lopez, Kith Pradhan, Orsolya Giricz, Goutham Ravipati, Li-Fan Wong, Sally Cole, Tushar D. Bhagat, Jonathan Feld, Yosman Dhar, Matthias Bartenstein, Victor J. Thiruthuvanathan, Amittha Wickrema, B. Hilda Ye, David A. Frank, Andrea Pellagatti, Jacqueline Boultwood, Tianyuan Zhou, Youngsoo Kim, A. Robert MacLeod, P.K. Epling-Burnette, Minwei Ye, Patricia McCoon, Richard Woessner, Ulrich Steidl, Britta Will, Amit Verma

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Figure 5

AZD9150 treatment leads to enhanced differentiation from primary MDS stem and progenitor cells.

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AZD9150 treatment leads to enhanced differentiation from primary MDS ste...
AZD9150 treatment leads to enhanced differentiation from primary MDS stem and progenitor cells. (A) Clonogenic assays from primary MDS mononuclear cell samples (n = 10) were performed, and cells were harvested after 14 days and assessed for differentiation by flow cytometry. An increase in erythroid (glycophorin A) and myeloid (CD11b) differentiation was seen in samples compared with controls. (B) A representative flow plot shows increased erythroid differentiation with an increase in the proerythroblasts and basophilic erythroblasts after AZD9150 treatment (10 μM). (C) The drug-treated colonies were also larger in size at the same magnification. Original magnification, 10×.