TY - JOUR
T1 - Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells
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
AU - Will, Britta
AU - Verma, Amit
N1 - Publisher Copyright:
Copyright 2018, American Society for Clinical Investigation.
PY - 2018/12/3
Y1 - 2018/12/3
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.
AB - 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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U2 - 10.1172/JCI120156
DO - 10.1172/JCI120156
M3 - Article
C2 - 30252677
AN - SCOPUS:85058331996
SN - 0021-9738
VL - 128
SP - 5489
EP - 5504
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -