tretinoin and Leukemia--Mast-Cell

Advanced systemic mastocytosis (SM) is a life-threatening neoplasm characterized by uncontrolled growth and accumulation of neoplastic mast cells (MCs) in various organs and a poor survival. So far, no curative treatment concept has been developed for these patients. We identified the epigenetic reader bromodomain-containing protein-4 (BRD4) as novel drug target in aggressive SM (ASM) and MC leukemia (MCL). As assessed by immunohistochemistry and PCR, neoplastic MCs expressed substantial amounts of BRD4 in ASM and MCL. The human MCL lines HMC-1 and ROSA also expressed BRD4, and their proliferation was blocked by a BRD4-specific short hairpin RNA. Correspondingly, the BRD4-targeting drug JQ1 induced dose-dependent growth inhibition and apoptosis in HMC-1 and ROSA cells, regardless of the presence or absence of KIT D816V. In addition, JQ1 suppressed the proliferation of primary neoplastic MCs obtained from patients with ASM or MCL (IC50: 100-500 nm). In drug combination experiments, midostaurin (PKC412) and all-trans retinoic acid were found to cooperate with JQ1 in producing synergistic effects on survival in HMC-1 and ROSA cells. Taken together, we have identified BRD4 as a promising drug target in advanced SM. Whether JQ1 or other BET-bromodomain inhibitors are effective in vivo in patients with advanced SM remains to be elucidated.

Topics: Antigens, CD; Apoptosis; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Humans; Leukemia, Mast-Cell; Nuclear Proteins; Proto-Oncogene Proteins c-kit; Receptors, Transferrin; Tetraspanin 30; Transcription Factors; Tretinoin; Triazoles

CD43 (leukosialin, sialophorin), a cell-surface associated mucin that is constitutively expressed at high levels on most leukocytes, is thought to be involved in cell activation and adhesion. We here provide evidence that the vitamin A metabolites all-trans and 13-cis retinoic acid up-regulate CD43 on human leukemic (HMC-1) mast cells, as determined by flow cytometry, Western blot analysis, and by semiquantitative reverse transcriptase-polymerase chain reaction. Enhanced CD43 expression was accompanied by a strong increase in anti-CD43-mediated, LFA-1-dependent homotypic aggregation of HMC-1 cells, demonstrating that newly synthesized CD43 is functionally active in transmitting signals across the plasma membrane which result in enhanced cellular adhesion. CD43 expression was also enhanced in response to retinoic acids on isolated human skin mast cells and human monocytes, but not on cells of the basophilic cell line KU-812 and promyelocytic HL-60 cells, indicating that these agents might act in a cell-type specific manner. These combined result-point to a novel aspect in the regulation of CD43. Possibly, vitamin A metabolites act directly on the CD43 gene, since putative retinoic acid response elements have been detected within its regulatory regions.

Topics: Antigens, CD; Cell Aggregation; Cells, Cultured; HL-60 Cells; Humans; Isotretinoin; Leukemia, Basophilic, Acute; Leukemia, Mast-Cell; Leukosialin; Lymphocyte Function-Associated Antigen-1; Mast Cells; Monocytes; Sialoglycoproteins; Skin; Tretinoin; Tumor Cells, Cultured; Up-Regulation