Distinct signaling events promote resistance to mitoxantrone and etoposide in pediatric AML: a Children’s Oncology Group report
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Xin Long1, Robert B. Gerbing3, Todd A. Alonzo3,4 and Michele S. Redell1,2
1Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
2Texas Children’s Hospital, Houston, TX, USA
3Children’s Oncology Group, Monrovia, CA, USA
4Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
Michele S. Redell, email: [email protected]
Keywords: marrow stroma, chemotherapy resistance, ERK1/2, DNA damage, myeloid leukemia
Received: May 07, 2017 Accepted: August 31, 2017 Published: September 28, 2017
Despite aggressive chemotherapy including mitoxantrone and etoposide, relapse occurs for almost half of children with acute myeloid leukemia (AML). Since both drugs inhibit topoisomerase II and cause DNA double strand breaks, resistance could be achieved by enhanced DNA damage repair (DDR), via homologous recombination (HR) and/or non-homologous end joining (NHEJ). An important source of extrinsic chemoresistance is the bone marrow stroma. We aimed to reveal intrinsic and stroma-induced signaling pathways that contribute to chemoresistance. Sixty diagnostic pediatric AML samples were cultured on or off stromal cells, with or without chemotherapy. We measured apoptosis, DNA damage signaling, and NHEJ/HR pathway activity by FACS analysis of intracellular cleaved PARP, γH2AX, pDNA-PKcs and pATM, respectively. Mitoxantrone strongly increased γH2AX and pDNA-PKcs. Neither chemotherapy drug induced pATM. DNA-PK inhibition alleviated mitoxantrone resistance for AML cells on and off stromal cells. Regarding stroma-induced signaling pathways, ERK1/2 was most consistently activated in primary AML cells by stromal cells. ERK1/2 inactivation partially restored chemosensitivity to AML cells on stromal cells. Additionally, low stroma-induced STAT3 activity and strong stroma-induced mitoxantrone resistance were associated with inferior clinical outcome. Taken together, the NHEJ DDR and ERK1/2 pathways are potential targets for reducing intrinsic and extrinsic chemotherapy resistance in pediatric AML.
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