ATRA and the specific RAR alpha agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells

作者：Chee L C Y; Hendy J; Purton L E; McArthur G A^*

来源：Leukemia, 2013, 27(6): 1369-1380.

DOI：10.1038/leu.2012.362

• AML1-ETO
• retinoids
• RAR alpha
• RAR gamma
• myeloid differentiation

All-trans retinoic acid (ATRA) is used successfully in the treatment of acute promyelocytic leukemia (APL). ATRA enhances hematopoietic stem cell self-renewal through retinoic acid receptor (RAR)gamma activation while promoting differentiation of committed myeloid progenitors through RAR alpha activation. Its lack of success in the treatment of non-APL acute myeloid leukemia (AML) may be related to ATRA's non-selectivity for the RAR alpha and RAR gamma isotypes, and specific RAR alpha activation may be more beneficial in promoting myeloid differentiation. To investigate this hypothesis, the effects of ATRA and the specific RAR alpha agonist NRX195183 was assessed in AML1-ETO (AE)-expressing murine bone marrow (BM) progenitors. ATRA potentiated the in vitro clonogenicity of these cells while NRX195183 had the opposite effect. Morphological and flow cytometric analysis confirmed a predominantly immature myeloid population in the ATRA-treated AE cells while the NRX195183-treated cells demonstrated an increase in the mature myeloid population. Similarly, NRX195183 treatment promoted myeloid differentiation in an AE9a in vivo murine model. In the ATRA-treated AE cells, gene expression analyses revealed functional networks involving SERPINE1 and bone morphogenetic protein 2; AKT phosphorylation was upregulated. Collectively, these findings confirm the contrasting roles of specific RAR alpha and RAR gamma activation in the clonogenicity and differentiation of AE cells with potential significant implications in the treatment of non-APL AML using a specific RAR alpha agonist.

• 出版日期2013-6