title: Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias.
abstract: As tyrosine kinase inhibitors (TKIs) fail to induce long-term response in blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL), novel therapies targeting leukemia-dysregulated pathways are necessary. Exportin-1 (XPO1), also known as chromosome maintenance protein 1, regulates cell growth and differentiation by controlling the nucleocytoplasmic trafficking of proteins and RNAs, some of which are aberrantly modulated in BCR-ABL1(+) leukemias. Using CD34(+) progenitors from CML, B-ALL, and healthy individuals, we found that XPO1 expression was markedly increased, mostly in a TKI-sensitive manner, in CML-BC and Ph(+) B-ALL. Notably, XPO1 was also elevated in Ph(-) B-ALL. Moreover, the clinically relevant XPO1 inhibitor KPT-330 strongly triggered apoptosis and impaired the clonogenic potential of leukemic, but not normal, CD34(+) progenitors, and increased survival of BCR-ABL1(+) mice, 50% of which remained alive and, mostly, became BCR-ABL1 negative. Moreover, KPT-330 compassionate use in a patient with TKI-resistant CML undergoing disease progression significantly reduced white blood cell count, blast cells, splenomegaly, lactate dehydrogenase levels, and bone pain. Mechanistically, KPT-330 altered the subcellular localization of leukemia-regulated factors including RNA-binding heterogeneous nuclear ribonucleoprotein A1 and the oncogene SET, thereby inducing reactivation of protein phosphatase 2A tumor suppressor and inhibition of BCR-ABL1 in CML-BC cells. Because XPO1 is important for leukemic cell survival, KPT-330 may represent an alternative therapy for TKI-refractory Ph(+) leukemias.
authors: Human Cancer Genetics Program, Department Molecular Virology Immunology and Medical Genetics.
authors: Christopher J
authors: CJ
authors: Walker
authors: Joshua J
authors: JJ
authors: Oaks
authors: Ramasamy
authors: R
authors: Santhanam
authors: Paolo
authors: P
authors: Neviani
authors: Jason G
authors: JG
authors: Harb
authors: Gregory
authors: G
authors: Ferenchak
authors: Justin J
authors: JJ
authors: Ellis
authors: Yosef
authors: Y
authors: Landesman
authors: Ann-Kathrin
authors: AK
authors: Eisfeld
authors: Nash Y
authors: NY
authors: Gabrail
authors: Carrie L
authors: CL
authors: Smith
authors: Michael A
authors: MA
authors: Caligiuri
authors: Peter
authors: P
authors: Hokland
authors: Denis Claude
authors: DC
authors: Roy
authors: Alistair
authors: A
authors: Reid
authors: Dragana
authors: D
authors: Milojkovic
authors: John M
authors: JM
authors: Goldman
authors: Jane
authors: J
authors: Apperley
authors: Ramiro
authors: R
authors: Garzon
authors: Guido
authors: G
authors: Marcucci
authors: Sharon
authors: S
authors: Shacham
authors: Michael G
authors: MG
authors: Kauffman
authors: Danilo
authors: D
authors: Perrotti
mesh_terms: D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D004268:DNA-Binding Proteins; D004353:Drug Evaluation, Preclinical; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D056488:Histone Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D000097606:Exportin 1 Protein
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; D056488:Histone Chaperones; D006834:Hydrazines; D028884:Karyopherins; D047428:Protein Kinase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D012261:Ribonucleoproteins; D014157:Transcription Factors; D014230:Triazoles; D000097606:Exportin 1 Protein; C581634:BCR-ABL1 fusion protein, human; C513473:SET protein, human; C585161:selinexor
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