MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model

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Pereira-Martins, Diego A. ; Weinhauser, Isabel ; Coelho-Silva, Juan Luiz ; Franca-Neto, Pedro L. ; Almeida, Luciana Y. ; Bianco, Thiago M. ; Silva, Cleide L. ; Franca, Rafael F. ; Traina, Fabiola ; Rego, Eduardo M. ; Schuringa, Jan Jacob ; Lucena-Araujo, Antonio R.

• Tipo de documento: Artigo Científico
• Fonte: CELL DEATH & DISEASE; v. 12, n. 4, p. 14-pg., 2021-04-06.

Resumo

Although the mixed lineage leukemia 5 (MLL5) gene has prognostic implications in acute promyelocyte leukemia (APL), the underlying mechanism remains to be elucidated. Here, we demonstrate the critical role exerted by MLL5 in APL regarding cell proliferation and resistance to drug-induced apoptosis, through mtROS regulation. Additionally, MLL5 overexpression increased the responsiveness of APL leukemic cells to all-trans retinoic acid (ATRA)-induced differentiation, via regulation of the epigenetic modifiers SETD7 and LSD1. In silico analysis indicated that APL blasts with MLL5(high) transcript levels were associated with retinoic acid binding and downstream signaling, while MLL5(low) blasts displayed decreased expression of epigenetic modifiers (such as KMT2C, PHF8 and ARID4A). Finally, APL xenograft transplants demonstrated improved engraftment of MLL5-expressing cells and increased myeloid differentiation over time. Concordantly, evaluation of engrafted blasts revealed increased responsiveness of MLL5-expressing cells to ATRA-induced granulocytic differentiation. Together, we describe the epigenetic changes triggered by the interaction of MLL5 and ATRA resulting in enhanced granulocytic differentiation. (AU)

• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 17/23117-1 - Avaliação da via TP53/TP73 na enxertia de células de leucemia promielocítica aguda em modelo de xenotransplante
• Beneficiário: Diego Antonio Pereira Martins
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 15/09228-0 - Detecção e estudo funcional de Macrofágos Associados a Tumor em um modelo transgênico de leucemia promielocítica aguda.
• Beneficiário: Isabel Weinhauser
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/23191-4 - Investigação da Participação de IRS2 na patogênese de neoplasias mieloproliferativas JAK2V617F utilizando modelos murinos
• Beneficiário: Juan Luiz Coelho da Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado