Downregulation of MTSS1 in acute myeloid leukemia is associated with a poor prognosis, chemotherapy resistance, and disease aggressiveness

Alexander Michael Grandits, Chi Huu Nguyen, Angela Schlerka, Hubert Hackl, Heinz Sill, Julia Etzler, Elizabeth Heyes, Dagmar Stoiber, Florian Grebien, Gerwin Heller, Rotraud Wieser

Research output: Journal article (peer-reviewed)Journal article

3 Citations (Scopus)

Abstract

Despite recent approval of targeted drugs for acute myeloid leukemia (AML) therapy, chemotherapy with cytosine arabinoside and anthracyclines remains an important pillar of treatment. Both primary and secondary resistance are frequent and associated with poor survival, yet the underlying molecular mechanisms are incompletely understood. In previous work, we identified genes deregulated between diagnosis and relapse of AML, corresponding to therapy naïve and resistant states, respectively. Among them was MTSS1, whose downregulation is known to enhance aggressiveness of solid tumors. Here we show that low MTSS1 expression at diagnosis was associated with a poor prognosis in AML. MTSS1 expression was regulated by promoter methylation, and reduced by cytosine arabinoside and the anthracycline daunorubicin. Experimental downregulation of MTSS1 affected the expression of numerous genes. It induced the DNA damage response kinase WEE1, and rendered human AML cell lines more resistant to cytosine arabinoside, daunorubicin, and other anti-cancer drugs. Mtss1 knockdown in murine MLL-AF9-driven AML substantially decreased disease latency, and increased leukemic burden and ex vivo chemotherapy resistance. In summary, low MTSS1 expression represents a novel factor contributing to disease aggressiveness, therapy resistance, and poor outcome in AML.

Original languageEnglish
Pages (from-to)2827-2839
Number of pages13
JournalLeukemia
Volume35
Issue number10
DOIs
Publication statusPublished - Oct 2021

Keywords

  • Animals
  • Anthracyclines/administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Biomarkers, Tumor/genetics
  • Cell Cycle Proteins/genetics
  • Cytarabine/administration & dosage
  • Daunorubicin/administration & dosage
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Myeloid, Acute/drug therapy
  • Mice, Inbred C57BL
  • Microfilament Proteins/genetics
  • Neoplasm Proteins/genetics
  • Prognosis
  • Protein-Tyrosine Kinases/genetics
  • Survival Rate

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