[Molecular diagnosis of and molecular targeting therapy for leukemia].
A number of molecular targets have been identified in leukemia, based on the understanding of signaling pathways controlling cell differentiation, proliferation, apoptosis, and malignant transformation. Growth factors and integrins interact with their receptors and activate signaling cascades with intimate interconnections. The specific niches within the bone marrow microenvironment may provide a sanctuary for subpopulations of leukemic cells to escape chemotherapy-induced death and acquire drug resistance. Investigations into bone marrow stroma-leukemia crosstalk may result in the development of strategies against the acquisition of a chemo-resistant phenotype and enhance the efficacy of therapies in leukemia. In recent studies, we proposed novel therapeutic interventions targeting the microenvironment/leukemia interaction focusing on SDF1/CXCR4, ILK/PI3K/Akt, TGF-beta, and Notch signaling. Gene transcriptional activity is regulated by chromatin modification and DNA methylation. Nuclear receptors such as RAR, RXR, and PPARgamma exert histone acetyl transferase activity (HAT). The transcription of target genes is initiated following the ligation of these receptors, recruitment of co-activators, and replacement of repressors. We demonstrated that histone acetylation by the PPARgamma agonist CDDO, RAR/RXR agonist ATRA, and/or histone deacetylase inhibitors (HDACIs) reversed the silenced RARbeta and MDR1 genes in acute promyelocytic leukemia, and that HDACI induced apoptosis with phagocytosis through the induction of Annexin A1 in AML1/ETO-positive acute myelocytic leukemia (AML) cells. The translation of research findings into effective clinical laboratory tests is an important approach. The flow cytometric technique is a powerful tool in the field of clinical laboratory medicine, with its accurate and rapid analysis. We carried out phospho-specific flow cytometry to investigate protein phosphorylation in AML cells and detect ZAP-70 in chronic lymphocytic leukemia cells, including the evaluation of antibodies, staining epitopes, fixing and permeabilizing methods, and analyzing systems. Finally, we emphasize the potential applications of research findings and methods in the fields of clinical medicine, molecular diagnosis, and targeting therapy.
Tabe
Yoko
Y
Department of Clinical Pathology, Juntendo University of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. tabe@juntendo.ac.jp