2013 OSU Molecular Life Sciences
Interdisciplinary Graduate Programs Symposium
Poster abstracts
Abstract:
As current treatments fail to induce long-term response in CML blast ciris (BC) and Philadelphia-chromosome positive (Ph+) ALL, novel therapies are necessary. We hypothesize that XPO1, which facilitates nuclear protein export, may contribute to Ph+ leukemogenesis, because it regulates cellular proliferation/survival, and many of the proteins it exports are tumor suppressors and leukemia-relevant proto-oncogenes (e.g. hnRNA A1, ABL1 and SET).
We found that compared to normal progenitors, XPO1 protein levels were elevated in CML and Ph+ ALL blasts. XPO1 inhibition by KPT-330 induced apoptosis and decreased clonogenic potential of CML and ALL blasts, but not normal progenitors, and treatment significantly increased survival of leukemic mice, 50% of which were alive after 16 weeks of treatment.
Mechanistically, KPT-330 treatment led to a nuclear accumulation of tumor suppressors (p53, p21, FOXO3A and IκB) and the proto-oncogene SET, which acts in the cytoplasm to inhibit the PP2A tumor suppressor. Accordingly, KPT-330 rescued PP2A activity and treatment of CML and Ph+ progenitors reduced BCR-ABL1 expression and activity. Finally, KPT-330 was administered (oral) to a CML-AP patient, as a run-in dose (12 mg/m2) for one week, then three therapeutic doses (16.5 mg/m2). After the first therapeutic dose there was a reduction in bone pain, immature myeloid, WBC count (>300,000 to 7000 cells/µL), splenomegaly (13cm to 4cm below costal margin), and serum lactate dehydrogenase (513 to 264 IU/L). One week after the last dose, WBC count increased to 37,000 cells/µL with reappearance of immature myeloid cells; however, the patient declined dose escalation. Therefore, XPO1 is necessary for the enhanced survival of Ph+ leukemic blasts, and KPT-330 may represent an effective treatment for TKI-refractory Ph+ leukemias.
Keywords: CML , XPO1