2. Academic Validation
  3. Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells

Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells

  • J Clin Invest. 2018 Dec 3;128(12):5479-5488. doi: 10.1172/JCI120156.
Aditi Shastri 1,  Gaurav Choudhary 1,  Margarida Teixeira 1,  Shanisha Gordon-Mitchell 1,  Nandini Ramachandra 1,  Lumie Bernard 1,  Sanchari Bhattacharyya 1,  Robert Lopez 1,  Kith Pradhan 1,  Orsolya Giricz 1,  Goutham Ravipati 1,  Li-Fan Wong 1,  Sally Cole 1,  Tushar D Bhagat 1,  Jonathan Feld 1,  Yosman Dhar 1,  Matthias Bartenstein 1,  Victor J Thiruthuvanathan 1,  Amittha Wickrema 2,  B Hilda Ye 1,  David A Frank 3,  Andrea Pellagatti 4,  Jacqueline Boultwood 4,  Tianyuan Zhou 5,  Youngsoo Kim 5,  A Robert MacLeod 5,  P K Epling-Burnette 6,  Minwei Ye 7,  Patricia McCoon 7,  Richard Woessner 7,  Ulrich Steidl 1,  Britta Will 1,  Amit Verma 1
Affiliations

Affiliations

  • 1 Albert Einstein College of Medicine, New York, New York, USA.
  • 2 University of Chicago, Chicago, Illinois, USA.
  • 3 Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 4 Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, and Oxford Biomedical Research Centre Haematology Theme, Oxford, United Kingdom.
  • 5 Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
  • 6 Moffit Cancer Center, University of South Florida, Tampa, Florida, USA.
  • 7 AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
PMID: 30252677 DOI: 10.1172/JCI120156
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.

Keywords

Hematology; Hematopoietic stem cells; Signal transduction; Stem cells.

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