Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling.
Leukemia
; 33(8): 1964-1977, 2019 08.
Article
in En
| MEDLINE
| ID: mdl-30842608
ABSTRACT
Tyrosine kinase inhibitor (TKI) therapy effectively blocks oncogenic Bcr-Abl signaling and induces molecular remission in the majority of CML patients. However, the disease-driving stem cell population is not fully targeted by TKI therapy in the majority of patients, and leukemic stem cells (LSCs) capable of re-inducing the disease can persist. In TKI-resistant CML, STAT3 inhibition was previously shown to reduce malignant cell survival. Here, we show therapy-resistant cell-extrinsic STAT3 activation in TKI-sensitive CML cells, using cell lines, HoxB8-immortalized murine BM cells, and primary human stem cells. Moreover, we identified JAK1 but not JAK2 as the STAT3-activating kinase by applying JAK1/2 selective inhibitors and genetic inactivation. Employing an IL-6-blocking peptide, we identified IL-6 as a mediator of STAT3 activation. Combined inhibition of Bcr-Abl and JAK1 further reduced CFUs from murine CML BM, human CML MNCs, as well as CD34+ CML cells, and similarly decreased LT-HSCs in a transgenic CML mouse model. In line with these observations, proliferation of human CML CD34+ cells was strongly reduced upon combined Bcr-Abl and JAK1 inhibition. Remarkably, the combinatory therapy significantly induced apoptosis even in quiescent LSCs. Our findings suggest JAK1 as a potential therapeutic target for curative CML therapies.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neoplastic Stem Cells
/
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
/
Signal Transduction
/
STAT3 Transcription Factor
/
Janus Kinase 1
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Leukemia
Journal subject:
HEMATOLOGIA
/
NEOPLASIAS
Year:
2019
Document type:
Article
Affiliation country:
Alemania