Details

Autor(en) / Beteiligte

• Walker, Christopher J.
• Oaks, Joshua J.
• Santhanam, Ramasamy
• Neviani, Paolo
• Harb, Jason G.
• Ferenchak, Gregory
• Ellis, Justin J.
• Landesman, Yosef
• Eisfeld, Ann-Kathrin
• Gabrail, Nash Y.
• Smith, Carrie L.
• Caligiuri, Michael A.
• Hokland, Peter
• Roy, Denis Claude
• Reid, Alistair
• Milojkovic, Dragana
• Goldman, John M.
• Apperley, Jane
• Garzon, Ramiro
• Marcucci, Guido
• Shacham, Sharon
• Kauffman, Michael G.
• Perrotti, Danilo

Titel

Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias

Ist Teil von

• Blood, 2013-10, Vol.122 (17), p.3034-3044

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •XPO1/CRM1 is upregulated in a BCR-ABL1 kinase-dependent and -independent manner and negatively controls PP2A tumor suppressor activity.•KPT-330 antagonizes survival of TKI-resistant Ph+ acute leukemias in vitro, in CML-BC animals, and in a CML-AP patient.