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Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models.
Minzel, Waleed; Venkatachalam, Avanthika; Fink, Avner; Hung, Eric; Brachya, Guy; Burstain, Ido; Shaham, Maya; Rivlin, Amitai; Omer, Itay; Zinger, Adar; Elias, Shlomo; Winter, Eitan; Erdman, Paul E; Sullivan, Robert W; Fung, Leah; Mercurio, Frank; Li, Dansu; Vacca, Joseph; Kaushansky, Nathali; Shlush, Liran; Oren, Moshe; Levine, Ross; Pikarsky, Eli; Snir-Alkalay, Irit; Ben-Neriah, Yinon.
Afiliación
  • Minzel W; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Venkatachalam A; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Fink A; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Hung E; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Brachya G; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Burstain I; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Shaham M; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Rivlin A; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Omer I; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Zinger A; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Elias S; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Hematology, Hadassah Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Winter E; Bioinformatics Unit of the I-CORE Computation Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Erdman PE; BioTheryX Inc., San Diego, CA, USA.
  • Sullivan RW; BioTheryX Inc., San Diego, CA, USA.
  • Fung L; BioTheryX Inc., San Diego, CA, USA.
  • Mercurio F; BioTheryX Inc., San Diego, CA, USA.
  • Li D; WuXi AppTec, Shanghai, China.
  • Vacca J; WuXi AppTec, Shanghai, China.
  • Kaushansky N; Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
  • Shlush L; Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
  • Oren M; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
  • Levine R; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Pikarsky E; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Pathology, Hadassah Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Snir-Alkalay I; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • Ben-Neriah Y; The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel. Electronic address: yinonb@ekmd.huji.ac.il.
Cell ; 175(1): 171-185.e25, 2018 09 20.
Article en En | MEDLINE | ID: mdl-30146162
CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2-/-;Flt3ITD AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Caseína Quinasa Ialfa Límite: Animals / Humans Idioma: En Revista: Cell Año: 2018 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Caseína Quinasa Ialfa Límite: Animals / Humans Idioma: En Revista: Cell Año: 2018 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos