TY - JOUR
T1 - Downregulation of MTSS1 in acute myeloid leukemia is associated with a poor prognosis, chemotherapy resistance, and disease aggressiveness
AU - Grandits, Alexander Michael
AU - Nguyen, Chi Huu
AU - Schlerka, Angela
AU - Hackl, Hubert
AU - Sill, Heinz
AU - Etzler, Julia
AU - Heyes, Elizabeth
AU - Stoiber, Dagmar
AU - Grebien, Florian
AU - Heller, Gerwin
AU - Wieser, Rotraud
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - Animals
KW - Anthracyclines/administration & dosage
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Biomarkers, Tumor/genetics
KW - Cell Cycle Proteins/genetics
KW - Cytarabine/administration & dosage
KW - Daunorubicin/administration & dosage
KW - Drug Resistance, Neoplasm
KW - Female
KW - Gene Expression Regulation, Leukemic
KW - Humans
KW - Leukemia, Myeloid, Acute/drug therapy
KW - Mice, Inbred C57BL
KW - Microfilament Proteins/genetics
KW - Neoplasm Proteins/genetics
KW - Prognosis
KW - Protein-Tyrosine Kinases/genetics
KW - Survival Rate
UR - http://www.scopus.com/inward/record.url?scp=85103234918&partnerID=8YFLogxK
U2 - 10.1038/s41375-021-01224-2
DO - 10.1038/s41375-021-01224-2
M3 - Journal article
C2 - 33782537
SN - 0887-6924
VL - 35
SP - 2827
EP - 2839
JO - Leukemia
JF - Leukemia
IS - 10
ER -