Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells

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 & 13 others 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 G. Steidl, Britta Will, Amit K. Verma

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5489-5504
Number of pages16
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

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Myelodysplastic Syndromes
Stem Cells
Acute Myeloid Leukemia
Myeloid Progenitor Cells
Antisense Oligonucleotides
Genes
Apoptosis
Cell Line
Growth
Population
AZD9150

ASJC Scopus subject areas

  • Medicine(all)

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Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells. / Shastri, Aditi; Choudhary, Gaurav; Teixeira, Margarida; Gordon-Mitchell, Shanisha; Ramachandra, Nandini; Bernard, Lumie; Bhattacharyya, Sanchari; Lopez, Robert; Pradhan, Kith; Giricz, Orsolya; Ravipati, Goutham; Wong, Li Fan; Cole, Sally; Bhagat, Tushar D.; Feld, Jonathan; Dhar, Yosman; Bartenstein, Matthias; Thiruthuvanathan, Victor J.; Wickrema, Amittha; Hilda Ye, B.; Frank, David A.; Pellagatti, Andrea; Boultwood, Jacqueline; Zhou, Tianyuan; Kim, Youngsoo; Robert MacLeod, A.; Epling-Burnette, P. K.; Ye, Minwei; McCoon, Patricia; Woessner, Richard; Steidl, Ulrich G.; Will, Britta; Verma, Amit K.

In: Journal of Clinical Investigation, Vol. 128, No. 12, 03.12.2018, p. 5489-5504.

Research output: Contribution to journalArticle

Shastri, A, Choudhary, G, Teixeira, M, Gordon-Mitchell, S, Ramachandra, N, Bernard, L, Bhattacharyya, S, Lopez, R, Pradhan, K, Giricz, O, Ravipati, G, Wong, LF, Cole, S, Bhagat, TD, Feld, J, Dhar, Y, Bartenstein, M, Thiruthuvanathan, VJ, Wickrema, A, Hilda Ye, B, Frank, DA, Pellagatti, A, Boultwood, J, Zhou, T, Kim, Y, Robert MacLeod, A, Epling-Burnette, PK, Ye, M, McCoon, P, Woessner, R, Steidl, UG, Will, B & Verma, AK 2018, 'Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells', Journal of Clinical Investigation, vol. 128, no. 12, pp. 5489-5504. https://doi.org/10.1172/JCI120156
Shastri A, Choudhary G, Teixeira M, Gordon-Mitchell S, Ramachandra N, Bernard L et al. Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells. Journal of Clinical Investigation. 2018 Dec 3;128(12):5489-5504. https://doi.org/10.1172/JCI120156
Shastri, Aditi ; Choudhary, Gaurav ; Teixeira, Margarida ; Gordon-Mitchell, Shanisha ; Ramachandra, Nandini ; Bernard, Lumie ; Bhattacharyya, Sanchari ; Lopez, Robert ; Pradhan, Kith ; Giricz, Orsolya ; Ravipati, Goutham ; Wong, Li Fan ; Cole, Sally ; Bhagat, Tushar D. ; Feld, Jonathan ; Dhar, Yosman ; Bartenstein, Matthias ; Thiruthuvanathan, Victor J. ; Wickrema, Amittha ; Hilda Ye, B. ; Frank, David A. ; Pellagatti, Andrea ; Boultwood, Jacqueline ; Zhou, Tianyuan ; Kim, Youngsoo ; Robert MacLeod, A. ; Epling-Burnette, P. K. ; Ye, Minwei ; McCoon, Patricia ; Woessner, Richard ; Steidl, Ulrich G. ; Will, Britta ; Verma, Amit K. / Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 12. pp. 5489-5504.
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AU - Shastri, Aditi

AU - Choudhary, Gaurav

AU - Teixeira, Margarida

AU - Gordon-Mitchell, Shanisha

AU - Ramachandra, Nandini

AU - Bernard, Lumie

AU - Bhattacharyya, Sanchari

AU - Lopez, Robert

AU - Pradhan, Kith

AU - Giricz, Orsolya

AU - Ravipati, Goutham

AU - Wong, Li Fan

AU - Cole, Sally

AU - Bhagat, Tushar D.

AU - Feld, Jonathan

AU - Dhar, Yosman

AU - Bartenstein, Matthias

AU - Thiruthuvanathan, Victor J.

AU - Wickrema, Amittha

AU - Hilda Ye, B.

AU - Frank, David A.

AU - Pellagatti, Andrea

AU - Boultwood, Jacqueline

AU - Zhou, Tianyuan

AU - Kim, Youngsoo

AU - Robert MacLeod, A.

AU - Epling-Burnette, P. K.

AU - Ye, Minwei

AU - McCoon, Patricia

AU - Woessner, Richard

AU - Steidl, Ulrich G.

AU - Will, Britta

AU - Verma, Amit K.

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N2 - 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.

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