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  1. Article ; Online: The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling.

    Stoner, Samuel A / Liu, Katherine Tin Heng / Andrews, Elizabeth T / Liu, Mengdan / Arimoto, Kei-Ichiro / Yan, Ming / Davis, Amanda G / Weng, Stephanie / Dow, Michelle / Xian, Su / DeKelver, Russell C / Carter, Hannah / Zhang, Dong-Er

    Blood cancer journal

    2020  Volume 10, Issue 2, Page(s) 16

    Abstract: Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal ...

    Abstract Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.
    MeSH term(s) Animals ; Biomarkers, Tumor/genetics ; Chromosomes, Human, Pair 21/genetics ; Chromosomes, Human, Pair 8/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Leukemia, Myeloid, Acute/prevention & control ; Mice ; Mice, Inbred C57BL ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Translocation, Genetic ; Tumor Cells, Cultured ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Xenograft Model Antitumor Assays ; rac GTP-Binding Proteins/genetics ; rac GTP-Binding Proteins/metabolism
    Chemical Substances Biomarkers, Tumor ; Oncogene Proteins, Fusion ; RASSF2 protein, human ; RUNX1-IT1 long non-coding RNA, human ; Tumor Suppressor Proteins ; rac GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2020-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2600560-8
    ISSN 2044-5385 ; 2044-5385
    ISSN (online) 2044-5385
    ISSN 2044-5385
    DOI 10.1038/s41408-020-0282-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Hippo kinase loss contributes to del(20q) hematologic malignancies through chronic innate immune activation.

    Stoner, Samuel A / Yan, Ming / Liu, Katherine Tin Heng / Arimoto, Kei-Ichiro / Shima, Takahiro / Wang, Huan-You / Johnson, Daniel T / Bejar, Rafael / Jamieson, Catriona / Guan, Kun-Liang / Zhang, Dong-Er

    Blood

    2019  Volume 134, Issue 20, Page(s) 1730–1744

    Abstract: Heterozygous deletions within chromosome 20q, or del(20q), are frequent cytogenetic abnormalities detected in hematologic malignancies. To date, identification of genes in the del(20q) common deleted region that contribute to disease development have ... ...

    Abstract Heterozygous deletions within chromosome 20q, or del(20q), are frequent cytogenetic abnormalities detected in hematologic malignancies. To date, identification of genes in the del(20q) common deleted region that contribute to disease development have remained elusive. Through assessment of patient gene expression, we have identified STK4 (encoding Hippo kinase MST1) as a 20q gene that is downregulated below haploinsufficient amounts in myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Hematopoietic-specific gene inactivation in mice revealed Hippo kinase loss to induce splenomegaly, thrombocytopenia, megakaryocytic dysplasia, and a propensity for chronic granulocytosis; phenotypes that closely resemble those observed in patients harboring del(20q). In a JAK2-V617F model, heterozygous Hippo kinase inactivation led to accelerated development of lethal myelofibrosis, recapitulating adverse MPN disease progression and revealing a novel genetic interaction between these 2 molecular events. Quantitative serum protein profiling showed that myelofibrotic transformation in mice was associated with cooperative effects of JAK2-V617F and Hippo kinase inactivation on innate immune-associated proinflammatory cytokine production, including IL-1β and IL-6. Mechanistically, MST1 interacted with IRAK1, and shRNA-mediated knockdown was sufficient to increase IRAK1-dependent innate immune activation of NF-κB in human myeloid cells. Consistent with this, treatment with a small molecule IRAK1/4 inhibitor rescued the aberrantly elevated IL-1β production in the JAK2-V617F MPN model. This study identified Hippo kinase MST1 (STK4) as having a central role in the biology of del(20q)-associated hematologic malignancies and revealed a novel molecular basis of adverse MPN progression that may be therapeutically exploitable via IRAK1 inhibition.
    MeSH term(s) Animals ; Chromosome Deletion ; Chromosomes, Human, Pair 20/genetics ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Hematologic Neoplasms/genetics ; Hematologic Neoplasms/immunology ; Humans ; Immunity, Innate ; Intracellular Signaling Peptides and Proteins ; Mice ; Myelodysplastic Syndromes/genetics ; Myelodysplastic Syndromes/immunology ; Myeloproliferative Disorders/genetics ; Myeloproliferative Disorders/immunology ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/immunology
    Chemical Substances Intracellular Signaling Peptides and Proteins ; Stk4 protein, mouse (EC 2.7.1.-) ; STK4 protein, human (EC 2.7.1.11) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2019-09-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2019000170
    Database MEDical Literature Analysis and Retrieval System OnLINE

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