Delta Np73 overexpression promotes resistance to apoptosis but does not cooperate with PML/RARA in the induction of an APL-leukemic phenotype

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Lucena-Araujo, Antonio R. ; Coelho-Silva, Juan L. ; Pereira-Martins, Diego A. ; Thome, Carolina ; Scheucher, Priscila S. ; Lange, Ana P. ; Paiva, Helder H. ; Hemmelgarn, Benjamin T. ; Morais-Sobral, Mariana C. ; Azevedo, Elisa A. ; Franca-Neto, Pedro L. ; Franca, Rafael F. ; Silva, Cleide L. ; Krause, Alexandre ; Rego, Eduardo M.

• Document type: Journal article
• Source: ONCOTARGET; v. 8, n. 5, p. 8475-8483, 2017.
• Web of Science Citations: 1

Abstract

Here, we evaluated whether the overexpression of transcriptionally inactive Delta Np73 cooperates with PML/RARA fusion protein in the induction of an APL-leukemic phenotype, as well as its role in vitro in proliferation, myeloid differentiation, and drug-induced apoptosis. Using lentiviral gene transfer, we showed in vitro that Delta Np73 overexpression resulted in increased proliferation in murine bone marrow (BM) cells from hCG-PML/RARA transgenic mice and their wild-type (WT) counterpart, with no accumulation of cells at G2/M or S phases; instead, Delta Np73-expressing cells had a lower rate of induced apoptosis. Next, we evaluated the effect of Delta Np73 on stem-cell self-renewal and myeloid differentiation. Primary BM cells lentivirally infected with human Delta Np73 were not immortalized in culture and did not present significant changes in the percentage of CD11b. Finally, we assessed the impact of Delta Np73 on leukemogenesis or its possible cooperation with PML/RARA fusion protein in the induction of an APL-leukemic phenotype. After 120 days of follow-up, all transplanted mice were clinically healthy and, no evidence of leukemia/myelodysplasia was apparent. Taken together, our data suggest that Delta Np73 had no leukemic transformation capacity by itself and apparently did not cooperate with the PML/RARA fusion protein to induce a leukemic phenotype in a murine BM transplantation model. In addition, the forced expression of Delta Np73 in murine BM progenitors did not alter the ATRA-induced differentiation rate in vitro or induce aberrant cell proliferation, but exerted an important role in cell survival, providing resistance to drug-induced apoptosis. (AU)

• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC