ABSTRACT
BACKGROUND: The interactions of acute lymphoblastic leukemia (ALL) blasts with bone marrow (BM) stromal cells have a positive impact on leukemia cell survival. In the present study, we proposed to identify and investigate the role of molecules critically involved in leukemia--microenvironment crosstalk. PROCEDURE: Gene expression profiling analyses of BM mesenchymal stem cells (BMMSC) were performed following stimulation by ALL cells. CCL2 and IL-8 plasma levels were evaluated from ALL patients and controls. Expression of the CCL2 and IL-8 receptors in ALL was determined by RT-PCR. The biological effects of CCL2, IL-8 or its neutralizing antibodies in primary precursor-B ALL and BMMSC cells were evaluated using in vitro assays. RESULTS: Leukemia stimulation of BMMSC upregulated the expression of several inflammatory chemokines, including CCL2 and IL-8. The BM plasma levels of CCL2 and IL-8 in children at diagnosis were significantly higher than in healthy controls (P < 0.001). Functional studies revealed that CCL2 and IL-8 enhanced the capacity of BMMSC to support adhesion of ALL cells. CCL2 and IL-8 were also found to enhance BMMSC survival and to increase their proliferation. ALL cells were not directly affected by CCL2 or IL-8. CONCLUSIONS: The leukemic BM microenvironment had increased levels of CCL2 and IL-8. These chemokines are known to have suppressive effects in normal hematopoiesis. Our data indicate that CCL2 and IL-8 have a positive impact on BMMSC survival, proliferation, and adhesiveness to ALL cells. Leukemia-associated CCL2 and IL-8 upregulation may represent one possible mechanism of microenvironment perversion in favor of ALL cells.
Subject(s)
Bone Marrow Cells/metabolism , Chemokine CCL2/metabolism , Interleukin-8/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Cell Adhesion , Cell Survival , Chemokine CCL2/genetics , Chemokine CCL2/physiology , Child , Child, Preschool , Female , Humans , Infant , Interleukin-8/genetics , Interleukin-8/physiology , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/physiopathology , Prognosis , Signal TransductionABSTRACT
PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Brazil , Child , Child, Preschool , Female , Humans , Infant , Male , Mercaptopurine/administration & dosage , Methotrexate/administration & dosage , Neoplasm Staging , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prospective Studies , Risk Factors , Survival Rate , Treatment OutcomeABSTRACT
Approximately 35% of T-cell acute lymphoblastic leukemia (T-ALL) cases have chromosomal translocations as evaluated by conventional cytogenetic methods (G-banding). Some chromosomal translocations are associated with morphologically and immunophenotypically distinct leukemia subtypes and define patients with different clinical outcomes. Chromosomal translocations may deregulate gene expression, thus contributing to the development of neoplasia, either by placing a putative oncogene under the control of strong regulatory elements or by generating chimeric genes and oncogenic fusion proteins. We report here a novel der(12)t(7;12)(p15;q24.3) in a child with T-ALL. Cloning and characterization of the breakpoint region may contribute to the discovery of new genes that are important in T-ALL.
