title: Activating c-KIT mutations confer oncogenic cooperativity and rescue RUNX1/ETO-induced DNA damage and apoptosis in human primary CD34+ hematopoietic progenitors.
abstract: The RUNX1/ETO (RE) fusion protein, which originates from the t(8;21) chromosomal rearrangement, is one of the most frequent translocation products found in de novo acute myeloid leukemia (AML). In RE leukemias, activated forms of the c-KIT tyrosine kinase receptor are frequently found, thereby suggesting oncogenic cooperativity between these oncoproteins in the development and maintenance of t(8;21) malignancies. In this report, we show that activated c-KIT cooperates with a C-terminal truncated variant of RE, REtr, to expand human CD34+ hematopoietic progenitors ex vivo. CD34+ cells expressing both oncogenes resemble the AML-M2 myeloblastic cell phenotype, in contrast to REtr-expressing cells which largely undergo granulocytic differentiation. Oncogenic c-KIT amplifies REtr-depended clonogenic growth and protects cells from exhaustion. Activated c-KIT reverts REtr-induced DNA damage and apoptosis. In the presence of activated c-KIT, REtr-downregulated DNA-repair genes are re-expressed leading to an enhancement of DNA-repair efficiency via homologous recombination. Together, our results provide new mechanistic insight into REtr and c-KIT oncogenic cooperativity and suggest that augmented DNA repair accounts for the increased chemoresistance observed in t(8;21)-positive AML patients with activated c-KIT mutations. This cell-protective mechanism might represent a new therapeutic target, as REtr cells with activated c-KIT are highly sensitive to pharmacological inhibitors of DNA repair.
authors.affiliation: 1] Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany [2] Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilian University Hospital, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Wichmann
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Quagliano-Lo Coco
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors.forename: Ö
authors.initials: Ö
authors.lastname: Yildiz
authors.affiliation: 1] Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany [2] Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilian University Hospital, Munich, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Chen-Wichmann
authors.affiliation: 1] Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany [2] BIOREN - CEGIN, Molecular Pathology Laboratory, Department of Pathology, School of Medicine, Universidad de La Frontera, Temuco, Chile.
authors.forename: H
authors.initials: H
authors.lastname: Weber
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Syzonenko
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe University, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Döring
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Brendel
authors.affiliation: 1] Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilian University Hospital, Munich, Germany [2] Institute of Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Ponnusamy
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kinner
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Brandts
authors.affiliation: 1] Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilian University Hospital, Munich, Germany [2] Institute of Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Henschler
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Grez
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D001549:Benzamides / Q000008:administration & dosage; D002453:Cell Cycle; D002469:Cell Separation; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D003001:Cloning, Molecular; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000737:chemistry; D005434:Flow Cytometry; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D000068877:Imatinib Mesylate; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage; D000075142:RUNX1 Translocation Partner 1 Protein; D014178:Translocation, Genetic; D020298:U937 Cells
chemical_list: C107844:AML1-ETO fusion protein, human; D018952:Antigens, CD34; D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit; D004791:Enzyme Inhibitors; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D000075142:RUNX1 Translocation Partner 1 Protein; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit