MIR-451 IS A NEW BIOMARKER THAT IDENTIFIES ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS WHO MAY BENEFIT FROM TREATMENT WITH NAMPT INHIBITORS
Author(s): ,
Keren Shichrur
Affiliations:
Pediatric Hematology Oncology,Schneider Children's Medical Center of Israel,Petah Tikva,Israel;Felsenstein Medical Research Center,Tel Aviv University,Tel Aviv ,Israel
,
Isaac Yaniv
Affiliations:
Pediatric Hematology Oncology,Schneider Children's Medical Center of Israel,Petah Tikva,Israel;Felsenstein Medical Research Center,Tel Aviv University,Tel Aviv,Israel
,
Jennifer Yarden
Affiliations:
Curewize Health Ltd.,Yokneam,Israel
Smadar Avigad
Affiliations:
Pediatric Hematology Oncology,Schneider Children's Medical Center of Israel,Petah Tikva,Israel;Felsenstein Medical Research Center,Tel Aviv University,Tel Aviv,Israel
EHA Learning Center. shichrur K. Jun 15, 2018; 214664
Keren shichrur
Keren shichrur

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Abstract: PF168

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
MicroRNAs (miRs) are a group of small noncoding RNAs that post-transcriptionally regulate gene expression by direct binding to their corresponding targets. Aberrant miR expression has been identified in various types of cancer playing essential roles in cancer initiation and progression. Thus, miRs represent a great potential as novel diagnostic and prognostic biomarkers of cancer as well as novel targets for cancer treatment. Previously we have demonstrated that low expression levels of miR-451 could act as a biomarker that could predict high risk of relapse in pediatric acute lymphoblastic leukemia (ALL) patients (Avigad et al. 2016). 

Aims
Our aim in this study was to explore the role of miR-451 and its target in ALL.

Methods

The relevance of various miR-451 expression levels on the growth rate of leukemic cells was evaluated using a xenograft mice model. A novel target of miR-451, identified by bioinformatic analysis, was validated for direct binding and regulation by miR-451 utilizing several putative assays. The correlation between miR-451 and it's novel target was studied also in other malignancies. Using this model we explored miR-451 as a biomarker for detecting the sensitivity to a specific pathway inhibitor of its target.

Results

We demonstrated that the growth rate of leukemic cells over expressing miR-451 was significantly reduced compared to miR-451 silenced cells in the mice (p=0.03). In this study, we identified an association between miR-451 and a putative target, NAMPT (Nicotinamide Phosphoribosyltransferase) which is a key enzyme in the NAD+ pathway. We detected a significant inverse correlation between miR-451 expression levels and NAMPT protein levels and provided evidence for the direct binding of miR-451 to NAMPT in ALL cell line. This correlation was also evident in other malignant cell lines such as breast, colon and prostate cancer cell lines. We used a mice xenograft ALL model to demonstrate the inverse correlation between miR-451 expression levels and the sensitivity to a potent NAMPT inhibitor (FK866). ALL cells expressing low levels of miR-451 demonstrated significantly increased sensitivity to treatment with the NAMPT inhibitor compared to high expressing cells. The sensitivity of each line to FK866 treatment was examined on a group of 89 mice. At the end of the experiments the mean tumor volume of the FK866 treated group injected with low miR-451 cells was 117 ±81mm3 compared to 1104 ±134mm3 in the non-treated group (p = 0.000118) while in the treated mice injected with high expressing cells the mean tumor volume was 544 ±64mm3 compared to 851 ±110mm3 in the non-treated group (p =0.028). This specific sensitivity was also evident in a prostate cancer xenograft model.

Conclusion

NAMPT was identified as a novel target of miR-451. miR-451 may play an important role in ALL progression via NAMPT regulation. Thus, miR-451 expression levels could be used as a biomarker for the identification of patients who may benefit from treatment with NAMPT inhibitors.

 

Session topic: 1. Acute lymphoblastic leukemia – Biology & Translational Research

Keyword(s): B cell acute lymphoblastic leukemia, Pediatric, Therapy

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