Treatment With Low-Dose Daunorubicin Reduces The Number Of Leukemia Stem Cells In Patients With Relapsed/Refractory Acute Myeloid Leukemia

Introduction: Patients with acute leukemia harbor a population of chemotherapy-resistant leukemia stem cells (LSC) which ultimately leads to disease relapse in many patients. In animal studies, we demonstrated that AKT-β-catenin interaction, indicated by Akt phosphorylation of β-catenin at serine 552 (pS552), was critical to LSC self-renewal and LSCs increased after cytotoxic chemotherapy. High throughput screening of over 1,100 FDA-approved compounds identified doxorubicin (DOX) and daunorubicin (DNR) as potent inhibitors of pS552. To better understand the role of DOX and DNR in specifically targeting LSC through pS552, we experimented with lower dosing schedules, recognizing that most AML patients receive high dose DNR, yet LSC persist and result in disease relapse. In a murine model, 1/40thof the conventional dose of DOX for 5 consecutive days (=1/8 total dose) decreased LSCs, increased hematopoetic stem cells and inhibited S552 phosphorylation in leukemic cells compared to baseline or post-chemotherapy. Using a phospho-specific monoclonal antibody, we tested 30 anonymized human leukemia specimens for immunohistochemical staining of β-catenin S552. Positive staining was seen in 18/30 patients with AML or ALL and supported inclusion of both AML and ALL in a pilot trial to test an inhibitor of β-catenin S552 phosphorylation.