Loss of function of TET2 cooperates with constitutively active KIT in murine and human models of mastocytosis.
Systemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM.
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Serena
S
De Vita
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Rebekka K
RK
Schneider
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Michael
M
Garcia
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Jenna
J
Wood
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Mathilde
M
Gavillet
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Benjamin L
BL
Ebert
Institute for Immunology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
Alexander
A
Gerbaulet
Institute for Immunology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
Axel
A
Roers
Human Oncology and Pathogenesis Program, and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Ross L
RL
Levine
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Ann
A
Mullally
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
David A
DA
Williams
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000069439:Dasatinib; D000077209:Decitabine; D049308:Dioxygenases; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020125:Mutation, Missense; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D034622:RNA Interference; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013270:Stomach / Q000473:pathology; D013844:Thiazoles / Q000627:therapeutic use
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D013844:Thiazoles; D000077209:Decitabine; D049308:Dioxygenases; C541081:TET2 protein, human; C551914:Tet2 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D001374:Azacitidine; D000069439:Dasatinib