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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Rego, E. M. ; Ruggero, D. ; Tribioli, C. ; Cattoretti, G. ; Kogan, S. ; Redner, R. L. ; Pandolfi, P. P.
Total Authors: 7
Document type: Journal article
Source: Oncogene; v. 25, n. 13, p. 1974-1979, Mar. 2006.
Field of knowledge: Biological Sciences - Genetics
Abstract

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)

FAPESP's process: 98/14247-6 - Center for Research on Cell-Based Therapy
Grantee:Marco Antonio Zago
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC