Open Collections

Gharaee, Nadia

University of British Columbia

Deletion of the long arm of chromosome 5 is the most common cytogenetic abnormality in myelodysplastic syndrome (MDS). Lenalidomide (LEN) is the first-line therapy for del(5q) MDS, but half of the patients become resistant within 2-3 years, highlighting the need for new treatment options. LEN binds to the substrate adaptor of CRL4CRBN E3 ubiquitin ligase, Cereblon, which leads to ubiquitination and degradation of CSNK1A1. CSNK1A1 is located on the commonly deleted region (CDR) of del(5q) MDS which makes del(5q) cells sensitive to further degradation of the protein. Formerly, we have shown that LEN resistance is associated with TP53 or RUNX1 loss-of-function mutations. The objective of this study is to attempt to overcome LEN resistance by finding other vulnerabilities in del(5q) MDS. We have previously shown that deficiency of miR-143 and miR-145, located on the CDR, results in myeloid expansion of hematopoietic stem cells. Since the locus of miR-143 and miR-145 differs from CSNK1A1, we hypothesized that dependencies based on miR-143 and miR-145 would be independent of CSNK1A1 haploinsufficiency. Our analysis identified the IGF-1 receptor (IGF-1R) as one of the putative targets of both miR-143 and miR-145. GSEA analysis on a previously published cohort of MDS patients showed that lower expression of miR-143 and miR-145 is associated with activation of the IGF-1 pathway. We hypothesize that the IGF-1R pathway is a potential target for LEN-resistant del(5q) MDS. We have confirmed the interaction of both miR-143 and miR-145 with IGF-1R mRNA using luciferase assays and RNA pulldown assays. Moreover, we have shown that inhibition of IGF-1R using BMS-536924 decreases cell viability of LEN-resistant del(5q) MDS-L cells (knocked out for either TP53 or RUNX1). Further, we evaluated the dependency of LEN-resistant del(5q) MDS-L cells on pathways regulating or regulated by IGF-1R including Abl signaling pathway and pathways downstream of IGF-1R. We have shown that the Abl and MAPK pathways are activated with low expression of miR-143 and miR-145. Furthermore, we demonstrated the efficacy of imatinib (Abl inhibitor) and trametinib (MEK1/2 inhibitor) in decreasing the viability of the LEN-resistant del(5q) MDS-L cell line. Thus, this work revealed novel targetable dependencies in LEN-resistant del(5q) MDS.

Text

2024-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/81849

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/