Two critical hits for promyelocytic leukemia

• Published in: Molecular cell Vol. 6; no. 5; pp. 1131 - 1141
• Main Authors: He, L Z, Bhaumik, M, Tribioli, C, Rego, E M, Ivins, S, Zelent, A, Pandolfi, P P
• Format: Journal Article
• Language: English
• Published: United States 01.11.2000
• Subjects: Animals; Apoptosis - drug effects; Cell Differentiation - drug effects; Cell Division - drug effects; Cell Survival - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Hematopoiesis - drug effects; Humans; Kruppel-Like Transcription Factors; Leukemia, Promyelocytic, Acute - genetics; Leukemia, Promyelocytic, Acute - metabolism; Leukemia, Promyelocytic, Acute - pathology; Mice; Mice, Transgenic; Mutation - genetics; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; PLZF gene; PML gene; Promyelocytic Leukemia Zinc Finger Protein; RAR^a gene; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - genetics; Repressor Proteins - metabolism; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - pathology; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Transgenes - genetics; Translocation, Genetic - genetics; Tretinoin - pharmacology
• ISSN: 1097-2765
• DOI: 10.1016/s1097-2765(00)00111-8

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations that always involve the RARalpha gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes). Due to the reciprocity of the translocation, X-RARalpha and RARalpha-X fusion proteins coexist in APL blasts. PLZF-RARalpha transgenic mice (TM) develop leukemia that lacks the differentiation block at the promyelocytic stage that characterizes APL. We generated TM expressing RARalpha-PLZF and PLZF-RARalpha in their promyelocytes. RARalpha-PLZF TM do not develop leukemia. However, PLZF-RARalpha/RARalpha-PLZF double TM develop leukemia with classic APL features. We demonstrate that RARalpha-PLZF can interfere with PLZF transcriptional repression and that this is critical for APL pathogenesis, since leukemias in PLZF(-/-)/PLZF-RARalpha mutants and in PLZF-RARalpha/RARalpha-PLZF TM are indistinguishable. Thus, both products of a cancer-associated translocation are crucial in determining the distinctive features of the disease.