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.

• Document type: Journal article
• Source: CELL DEATH & DISEASE; v. 12, n. 4, p. 14-pg., 2021-04-06.

Abstract

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)

• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/23117-1 - Evaluation of TP53/TP73 pathway in engraftment of acute promyelocytic leukemia cells in xenotransplantation model
• Grantee: Diego Antonio Pereira Martins
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/09228-0 - Detection and functional analysis of Tumor-Associated Macrophages (TAM) in a transgenic model of acute promyelocytic leukemia (APL).
• Grantee: Isabel Weinhauser
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/23191-4 - Investigation of IRS2 role on the pathogenesis of myeloproliferative neoplasms JAK2V617F using murine models
• Grantee: Juan Luiz Coelho da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate