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      headline:Haploinsufficiency of miR-143 and miR-145 reveal targetable dependencies in resistant del(5q) myelodysplastic neoplasm
      description:Myelodysplastic neoplasms (MDS) are stem cell disorders characterized by ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). Chromosomal alterations are frequent in MDS, with interstitial deletion of chromosome 5q (del(5q)) being the most common. Lenalidomide is the current first-line treatment for del(5q) MDS and its efficacy relies on degradation of CK1α which is encoded by the CSNK1A1 gene located in the commonly deleted region (CDR) of chromosome 5q. However, lenalidomide-resistance is common, often secondary to loss-of-function mutations in TP53 or RUNX1. The CDR in del(5q) harbors several genes, including noncoding miRNAs, the loss of which contribute to disease phenotypes. miR-143 and miR-145 are located within the del(5q) CDR, but precise understanding of their role in human hematopoiesis and in the pathogenesis of del(5q) MDS is lacking. Here we provide evidence that deficiency of miR-143 and miR-145 plays a role in clonal expansion of del(5q) MDS. We show that insulin-like growth factor 1 receptor (IGF-1R) is a direct target of both miR-143 and miR-145. Our data demonstrate that IGF-1R inhibition reduces proliferation and viability of del(5q) cells in vitro and in vivo, and that lenalidomide-resistant del(5q) MDS cells depleted of either TP53 or RUNX1 are sensitive to IGF-1R inhibition. Resistant del(5q) MDS-L cells, as well as primary MDS marrow cells, are also sensitive to targeting of IGF-1R-related dependencies in del(5q) MDS, which include the Abl and MAPK signaling pathways. This work thus provides potential new therapeutic avenues for lenalidomide-resistant del(5q) MDS.
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         name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
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         name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
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            address:
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            address:
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               type:PostalAddress
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            address:
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            address:
               name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
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            address:
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            address:
               name:Leukemia/BMT Program of BC, BC Cancer and Vancouver Coastal Health, Vancouver, Canada
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            address:
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            address:
               name:Department of Haematology, Royal Adelaide Hospital, Adelaide, Australia
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            address:
               name:Department of Haematology, Royal Adelaide Hospital, Adelaide, Australia
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            address:
               name:Moffitt Cancer Center, Tampa, USA
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            address:
               name:Moffitt Cancer Center, Tampa, USA
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      name:Eric Padron
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      affiliation:
            name:Moffitt Cancer Center
            address:
               name:Moffitt Cancer Center, Tampa, USA
               type:PostalAddress
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      name:Yu Deng
      affiliation:
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            address:
               name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
               type:PostalAddress
            type:Organization
            name:University of British Columbia
            address:
               name:Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
               type:PostalAddress
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      name:Gary Cole
      affiliation:
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            address:
               name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
               type:PostalAddress
            type:Organization
      name:Patricia Umlandt
      affiliation:
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            address:
               name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
               type:PostalAddress
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      name:Megan Fuller
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            address:
               name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
               type:PostalAddress
            type:Organization
      name:Ada Kim
      affiliation:
            name:BC Cancer Research Institute
            address:
               name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
               type:PostalAddress
            type:Organization
      name:Aly Karsan
      url:http://orcid.org/0000-0001-6753-892X
      affiliation:
            name:BC Cancer Research Institute
            address:
               name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
               type:PostalAddress
            type:Organization
            name:University of British Columbia
            address:
               name:Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Leukemia/BMT Program of BC, BC Cancer and Vancouver Coastal Health, Vancouver, Canada
      name:Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada
      name:Department of Haematology, Royal Adelaide Hospital, Adelaide, Australia
      name:Department of Haematology, Royal Adelaide Hospital, Adelaide, Australia
      name:Moffitt Cancer Center, Tampa, USA
      name:Moffitt Cancer Center, Tampa, USA
      name:Moffitt Cancer Center, Tampa, USA
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
      name:Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

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