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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 Stem cells

Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells

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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 4

AZD9150 is rapidly incorporated by primary MDS/AML stem and progenitor cells and leads to STAT3 inhibition.

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AZD9150 is rapidly incorporated by primary MDS/AML stem and progenitor c...
MDS/AML–derived stem and progenitor cells were treated with AZD9150 (2.5 μM, 10 μM) and then assessed for uptake of the oligonucleotide after assessment by intracellular flow cytometry with antibody against the oligonucleotide backbone. (A–D) Both progenitors and stem cells incorporated AZD9150 by 24 hours. (E) The uptake was greater in MD/AML stem cells compared with cord blood controls. (F) STAT3 expression as measured by qPCR was significantly decreased in MDS/AML stem cells (n = 6) compared with cord blood (CB) stem cell controls (n = 6) after treatment with AZD9150. (Two-tailed t test for all, *P < 0.05.)
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