Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia

Cancer Cell International

Research

José M. Carbó¹  Ruth M. Risueño¹  Josep M. Cornet-Masana¹  Antònia Banús-Mulet¹  Jordi Esteve²  Francesca Guijarro²  Laia Cuesta-Casanovas³  Jennifer Delgado-Martínez⁴ 

[1] Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-GTP, Crta Can Ruti, Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain;Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-GTP, Crta Can Ruti, Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain;Department of Hematology, Hospital Clínic, Barcelona, Spain;Faculty of Medicine, University of Barcelona, Barcelona, Spain;Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-GTP, Crta Can Ruti, Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain;Faculty of Biosciences, Autonomous University of Barcelona, Barcelona, Spain;Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-GTP, Crta Can Ruti, Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain;Faculty of Pharmacy, University of Barcelona, Barcelona, Spain;

关键词: Prolactin receptor;    Leukemia;    Senescence;    Biomarker;    Differentiation;   

DOI  :  10.1186/s12935-023-02944-4

 received in 2023-02-21, accepted in 2023-05-11,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundDevelopment of precision medicine requires the identification of easily detectable and druggable biomarkers. Despite recent targeted drug approvals, prognosis of acute myeloid leukemia (AML) patients needs to be greatly improved, as relapse and refractory disease are still difficult to manage. Thus, new therapeutic approaches are needed. Based on in silico-generated preliminary data and the literature, the role of the prolactin (PRL)-mediated signaling was interrogated in AML.MethodsProtein expression and cell viability were determined by flow cytometry. Repopulation capacity was studied in murine xenotransplantation assays. Gene expression was measured by qPCR and luciferase-reporters. SA-β-Gal staining was used as a senescence marker.ResultsThe prolactin receptor (PRLR) was upregulated in AML cells, as compared to their healthy counterpart. The genetic and molecular inhibition of this receptor reduced the colony-forming potential. Disruption of the PRLR signaling, either using a mutant PRL or a dominant-negative isoform of PRLR, reduced the leukemia burden in vivo, in xenotransplantation assays. The expression levels of PRLR directly correlated with resistance to cytarabine. Indeed, acquired cytarabine resistance was accompanied with the induction of PRLR surface expression. The signaling associated to PRLR in AML was mainly mediated by Stat5, in contrast to the residual function of Stat3. In concordance, Stat5 mRNA was significantly overexpressed at mRNA levels in relapse AML samples. A senescence-like phenotype, measured by SA-β-gal staining, was induced upon enforced expression of PRLR in AML cells, partially dependent on ATR. Similar to the previously described chemoresistance-induced senescence in AML, no cell cycle arrest was observed. Additionally, the therapeutic potential of PRLR in AML was genetically validated.ConclusionsThese results support the role of PRLR as a therapeutic target for AML and the further development of drug discovery programs searching for specific PRLR inhibitors.

【 授权许可】

CC BY   
© The Author(s) 2023

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