Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells
Aditi Shastri, … , Britta Will, Amit Verma
Aditi Shastri, … , Britta Will, Amit Verma
Published December 3, 2018; First published September 25, 2018
Citation Information: J Clin Invest. 2018;128(12):5479-5488. https://doi.org/10.1172/JCI120156.
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Categories: Research Article Hematology Stem cells

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 1

STAT3 is overexpressed in MDS and AML HSCs and progenitors and is associated with worse prognosis.

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STAT3 is overexpressed in MDS and AML HSCs and progenitors and is associ...
(A–D) Gene expression data from sorted MDS/AML bone marrow samples were compared with data from healthy controls (Ctrl) and revealed significantly increased STAT3 expression in LT-HSCs (Lin–, CD34+, CD38–, CD90–, n = 12 MDS/AML, healthy control [HC] = 4), ST-HSCs (Lin–, CD34+, CD38–, CD90), and GMPs (Lin–, CD34+, CD38+, CD90+, CD123+) (P < 0.001, FDR < 5%). (E and F) Cytogenetic abnormalities are depicted as: NK, normal karyotype; CK, complex karyotype; –7, deletion of chromosome 7. “Ctrl” refers to healthy control sorted populations. qPCR on an independent cohort of sorted cells from controls and MDS and AML samples reveals increased expression of STAT3 in MDS/AML HSCs (LT/ST) and GMPs. (G) Survival of 183 MDS patients was correlated with STAT3 expression in marrow-derived CD34+ cells. Patients with higher STAT3 levels (greater than median) had a median survival of 2.6 years compared with 5.8 years for the group with lower STAT3 (log-rank P < 0.01). (H–J) Patients with high STAT3 expression also had significantly reduced mean hemoglobin levels, a higher blast percentage, and increased transfusion dependence. Test of proportions, *P < 0.05.