Crosstalk between hnRNP K and SET in ATRA‐induced differentiation in acute promyelocytic leukemia
Karina Stringhetta Padovani,
Renata Nishida Goto,
Lais Brigliadori Fugio,
Cristiana Bernadelli Garcia,
Vani Maria Alves,
Maria Sol Brassesco,
Lewis Joel Greene,
Eduardo Magalhães Rego,
Andréia Machado Leopoldino
Affiliations
Karina Stringhetta Padovani
Department of Clinical Analyses, Toxicology and Food Sciences School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Brazil
Renata Nishida Goto
Department of Clinical Analyses, Toxicology and Food Sciences School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Brazil
Lais Brigliadori Fugio
Department of Clinical Analyses, Toxicology and Food Sciences School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Brazil
Cristiana Bernadelli Garcia
Department of Clinical Analyses, Toxicology and Food Sciences School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Brazil
Vani Maria Alves
Department of Cellular and Molecular Biology and Pathogenic Bioagents School of Medicine of Ribeirão Preto‐FMRP University of São Paulo Ribeirão Preto Brazil
Maria Sol Brassesco
Department of Biology Faculty of Philosophy, Sciences and Letters of Ribeirão Preto University of São Paulo Brazil
Lewis Joel Greene
CEPID‐FAPESP Center for Cell Based Therapy Regional Blood Center of Ribeirão Preto Brazil
Eduardo Magalhães Rego
CEPID‐FAPESP Center for Cell Based Therapy Regional Blood Center of Ribeirão Preto Brazil
Andréia Machado Leopoldino
Department of Clinical Analyses, Toxicology and Food Sciences School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Brazil
HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all‐trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA‐induced differentiation in APL. We observed higher (5‐ to 40‐fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short‐hairpin RNA led to cell death in ATRA‐sensitive NB4 and resistant NB4‐R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4‐R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis‐specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4‐R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4‐R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance.
