ABSTRACT
CXCR4 is a key player in the retention and survival of human acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment. We studied the effects of the CXCR4 antagonist BL-8040 on the survival of AML blasts, and investigated the molecular mechanisms by which CXCR4 signaling inhibition leads to leukemic cell death. Treatment with BL-8040 induced the robust mobilization of AML blasts from the BM. In addition, AML cells exposed to BL-8040 underwent differentiation. Furthermore, BL-8040 induced the apoptosis of AML cells in vitro and in vivo. This apoptosis was mediated by the upregulation of miR-15a/miR-16-1, resulting in downregulation of the target genes BCL-2, MCL-1 and cyclin-D1. Overexpression of miR-15a/miR-16-1 directly induced leukemic cell death. BL-8040-induced apoptosis was also mediated by the inhibition of survival signals via the AKT/ERK pathways. Importantly, treatment with a BCL-2 inhibitor induced apoptosis and act together with BL-8040 to enhance cell death. BL-8040 also synergized with FLT3 inhibitors to induce AML cell death. Importantly, this combined treatment prolonged the survival of tumor-bearing mice and reduced minimal residual disease in vivo. Our results provide a rationale to test combination therapies employing BL-8040 and BCL-2 or FLT3 inhibitors to achieve increased efficacy of these agents.
Subject(s)
Apoptosis/drug effects , Cyclin D1/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Leukemia, Myeloid, Acute/pathology , MicroRNAs/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Peptides/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, CXCR4/antagonists & inhibitors , Cell Line, Tumor , Down-Regulation , Humans , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/metabolism , Real-Time Polymerase Chain ReactionSubject(s)
Janus Kinase 2/genetics , Lymphocyte Transfusion , Mutation , Peripheral Blood Stem Cell Transplantation , Polycythemia Vera/therapy , Polymerase Chain Reaction/methods , Primary Myelofibrosis/therapy , Humans , Male , Middle Aged , Polycythemia Vera/genetics , Primary Myelofibrosis/genetics , Recurrence , Transplantation, HomologousABSTRACT
BACKGROUND: Very elderly patients (> or =80 years old) with non-Hodgkin's lymphoma (NHL) frequently have co-morbid conditions and are generally excluded from clinical trials or even from treatment. The optimal treatment of these patients is unknown. PATIENTS AND METHODS: We reviewed the records of 109 patients > or =80 years at diagnosis of NHL (65 F/44 M; median age: 84 years, range; 80-95). RESULTS: Seventy-eight patients (72%) had aggressive NHL, 25 (23%) had indolent and NHL, eight had unclassified disease. Advanced-stage disease was noted in 54%. Forty patients (39%) had a poor ECOG performance status (PS), and 52 (49%) had an intermediate or high risk International Prognostic Index (IPI). Seventy-nine patients (72%) were treated with chemotherapy and 37 (34%) with radiotherapy. Initial chemotherapy consisted of chlorambucil in 15, oral etoposide in 2, and combination protocol in 62. Only 16% of patients received full-dose therapy, and only 50% completed > or =6 cycles of combination chemotherapy. The overall response rate for the 69 evaluable patients was 84% (complete 56.5%, partial 27.5%). Overall 5-year survival for the whole group was 39%, and median survival time was 26 months. CONCLUSION: A high response rate can be achieved in very elderly NHL patients despite aggressive histology, poor prognostic features, and reduced doses of chemotherapy. Age alone should not be a contraindication to treatment.