Hippo kinase loss contributes to del(20q) hematologic malignancies through chronic innate immune activation

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 kinaseMST1) as a 20q gene that is downregulated below haploinsufficient amounts in myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Hematopoieticspecific 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 associatedwith cooperative effects of JAK2-V617F and Hippo kinase inactivation on innate immune-associated proinflammatory cytokine production, including IL-1b and IL-6. Mechanistically, MST1 interacted with IRAK1, and shRNA-mediated knockdown was sufficient to increase IRAK1-dependent innate immune activation of NF-kB in human myeloid cells. Consistent with this, treatment with a small molecule IRAK1/4 inhibitor rescued the aberrantly elevated IL-1b 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 hematologicmalignancies and revealed a novelmolecular basis of adverse MPN progression that may be therapeutically exploitable via IRAK1 inhibition.

Original languageEnglish
Pages (from-to)1730-1744
Number of pages15
JournalBlood
Volume134
Issue number20
DOIs
Publication statusPublished - Nov 14 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Hippo kinase loss contributes to del(20q) hematologic malignancies through chronic innate immune activation'. Together they form a unique fingerprint.

  • Cite this

    Stoner, S. A., Yan, M., Liu, K. T. H., Arimoto, K. I., Shima, T., Wang, H. Y., Johnson, D. T., Bejar, R., Jamieson, C., Guan, K. L., & Zhang, D. E. (2019). Hippo kinase loss contributes to del(20q) hematologic malignancies through chronic innate immune activation. Blood, 134(20), 1730-1744. https://doi.org/10.1182/blood.2019000170