lithium-chloride and Leukemia--Myeloid

Exogenous expression of the transcription factor Scl (Tal1) in WEHI-3B D+ myelomonocytic leukemia cells interferes with their capacity to respond to all-trans retinoic acid (ATRA) induced differentiation; combination of ATRA with LiCl, however, circumvents the inhibition of differentiation produced by Scl. To gain information on the possible involvement of this transcription factor in the non-responsiveness of acute myelocytic leukemia (AML) patients to ATRA, we compared the endogenous expression levels of Scl and its transcription complex partners [i.e., Rbtn1 (LMO1), Rbtn2 (LMO2), Ldb1, and GATA family proteins] in leukemic blast cells from patients with AML and acute promyelocytic leukemia (APL), and determined the effects of lithium chloride alone or in combination with ATRA on the capacity of blast cells to differentiate during short-term ex vivo culture. Levels of Scl, Rbtn2, GATA1, and Ldb1 expression were comparable in AML and APL blasts, while the levels of expression of Rbtn1, GATA2, and GATA3 were absent or markedly lower in APL cells. Differentiation markers (cell surface myeloid antigens CD11b, CD15, CD14, and CD33) were also analyzed in blast cells. ATRA produced changes in at least one surface antigen differentiation marker in 89% of patient blasts, while LiCl caused such changes in 72% of the leukemic cells of patients. The combination of LiCl and ATRA induced the differentiation of leukemic blasts from 94% of patients. Although the expression of the transcription factors did not act as individual predictors of responsiveness or non-responsiveness to the inducers of differentiation, ATRA or ATRA plus LiCl, the addition of LiCl to ATRA increased the differentiation response over that of ATRA alone in a number of leukemic samples. These findings suggest that the combination of LiCl and ATRA may produce some clinical benefit in the treatment of the myeloid leukemias.

Topics: Acute Disease; Adult; Aged; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Bone Marrow Cells; Cell Differentiation; DNA Primers; DNA-Binding Proteins; Female; Flow Cytometry; Humans; Leukemia, Myeloid; Lithium Chloride; Male; Middle Aged; Proto-Oncogene Proteins; T-Cell Acute Lymphocytic Leukemia Protein 1; Transcription Factors; Tretinoin

The WEHI-3B D+ leukemia is a near-diploid differentiation-competent cell line that undergoes myeloid differentiation in response to retinoic acid. WEHI-3B D- cells, derived from WEHI-3B D+ cells, are near tetraploid and not responsive to the differentiation-inducing properties of the retinoid. To gain information on mechanisms that regulate the maturation of these two cell lines, several multiploid cell lines have been established through fusion of WEHI-3B D+ and WEHI-3B D- cells. Studies with the multiploid cell lines have shown that (a) the cellular growth rate decreases with increased DNA ploidy; (b) near-tetraploid D+/+ cells, obtained by fusing WEHI-3B D+ with WEHI-3B D+ cells, remain differentiation-competent, demonstrating that no direct relationship exists between differentiation competency and DNA ploidy; and (c) near-hexaploid D +/- and D -/+ cells, formed by fusion of WEHI-3B D+ with WEHI-3B D- cells, do not respond to differentiation inducers, suggesting the inhibition of the differentiation machinery of WEHI-3B D+ cells by components from maturation-incompetent WEHI-3B D- cells. The scl transcription factor gene is expressed in WEHI-3B D- cells and is absent in WEHI-3B D+ cells. Overexpression of scl by transfection of scl cDNA in WEHI-3B D+ cells markedly decreased the capacity of retinoic acid to induce differentiation, suggesting that scl functions as a repressor of differentiation in WEHI-3B cell lines.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Division; Cell Fusion; Cell Size; Cholecalciferol; Diploidy; DNA-Binding Proteins; Gene Expression; Granulocyte Colony-Stimulating Factor; Leukemia, Myeloid; Lithium Chloride; Mice; Polyploidy; Proto-Oncogene Proteins; RNA, Messenger; RNA, Neoplasm; T-Cell Acute Lymphocytic Leukemia Protein 1; Transcription Factors; Transfection; Tretinoin; Tumor Cells, Cultured

The effect of lithium on normal and chronic granulocytic leukemia (CGL) granulo-monocytic precursors (CFU-GM) has been studied. Lithium slightly increases normal CFU-GM growth whereas it is without effect or moderately inhibitory for CGL CFU-GM. It is suggested that it is unlikely that lithium therapy enhances the proliferation of a silent leukemic clone.

Topics: Bone Marrow; Chlorides; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; Lithium; Lithium Chloride