Leukemia with distinct phenotypes in transgenic mice expressing PML/ RAR alpha, PLZF/RAR alpha or NPM/RAR alpha

Autor(es)

Rego, E. M. ; Ruggero, D. ; Tribioli, C. ; Cattoretti, G. ; Kogan, S. ; Redner, R. L. ; Pandolfi, P. P.

• Tipo de documento: Artigo Científico
• Fonte: Oncogene; v. 25, n. 13, p. 1974-1979, Mar. 2006.
• Área do conhecimento: Ciências Biológicas - Genética
• Assunto(s): Genética médica Neoplasias Leucemia promielocítica aguda

Resumo

Recurrent chromosomal translocations involving the RAR-ALPHA locus on chromosome 17 are the hallmark of acute promyelocytic leukemia (APL). The RAR-ALPHA gene fuses to variable partners (PML, PLZF, NPM, NuMA and STAT5B: X genes) leading to the expression of APL-specific fusion proteins with identical RAR-ALPHA moieties. To analyse whether the variable X moiety could affect the activity of the fusion protein in vivo, we generated and characterized, on a comparative basis, NPM/RAR-ALPHA transgenic mice (TM) in which the fusion gene is expressed under the control of a human Cathepsin G (hCG) minigene. We compared the features of the leukemia observed in these TM with those in hCG-PML/RAR-ALPHA and hCG-PLZF/RAR-ALPHA TM. In all three transgenic models, leukemia developed after a variably long latency, with variable penetrance. However, the three leukemias displayed distinct cytomorphological features. hCG-NPM/RAR-ALPHA leukemic cells resembled monoblasts. This phenotype contrasts with what was observed in the hCG-PML/RAR-ALPHA TM model in which the leukemic phase was characterized by the proliferation of promyelocytic blasts. Similarly, hCG-PLZF/RAR-ALPHA TM displayed a different phenotype where terminally differentiated myeloid cells predominated. Importantly, the NPM/RAR-ALPHA oncoprotein was found to localize in the nucleolus, unlike PML/RAR-ALPHA and PLZF/RAR-ALPHA, thus possibly interfering with the normal function of NPM. Similarly to what was observed in human APL patients, we found that NPM/ RAR-ALPHA and PML/RAR-ALPHA, but not PLZF/RAR-ALPHA leukemia, was responsive to all-trans retinoic acid (ATRA) or As2O3 treatments. Taken together, our results underscore the critical relevance of the X moiety in dictating the biology of the disease and the activity of the APL fusion oncoprotein. (AU)

• Processo FAPESP: 98/14247-6 - Center for Research on Cell-Based Therapy
• Beneficiário: Marco Antonio Zago
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs