1. Academic Validation
  2. ALCAM regulates multiple myeloma chemoresistant side population

ALCAM regulates multiple myeloma chemoresistant side population

  • Cell Death Dis. 2022 Feb 10;13(2):136. doi: 10.1038/s41419-022-04556-8.
Fangfang Wang  # 1 Zhang Dan  # 1 Hongmei Luo  # 1 Jingcao Huang 1 Yushan Cui 1 Hong Ding 1 Juan Xu 1 Zhimei Lin 1 2 Yuhan Gao 1 Xinyu Zhai 1 Yan Yang 1 Ying Qu 1 Li Zhang 1 Fengjiao Chen 1 Qiang Wang 3 Xin Wang 1 Yu Feng 1 Ting Liu 1 Qing Yi 3 Ting Niu 4 Yuhuan Zheng 5
Affiliations

Affiliations

  • 1 Department of Hematology, West China Hospital/State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China.
  • 2 Department of Hematology, The Affiliated Hospital of Chengdu University, Chengdu, China.
  • 3 Center for Translational Research in Hematological Malignancies, Cancer Center, Houston Methodist Hospital, Houston, TX, USA.
  • 4 Department of Hematology, West China Hospital/State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China. zhengyuhuan@scu.edu.cn.
  • 5 Department of Hematology, West China Hospital/State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China. tingniu@sina.com.
  • # Contributed equally.
Abstract

Drug-resistance is a major problem preventing a cure in patients with multiple myeloma (MM). Previously, we demonstrated that activated-leukocyte-cell-adhesion-molecule (ALCAM) is a prognostic factor in MM and inhibits EGF/EGFR-initiated MM clonogenicity. In this study, we further showed that the ALCAM-EGF/EGFR axis regulated the MM side population (SP)-mediated drug-resistance. ALCAM-knockdown MM cells displayed an enhanced ratio of SP cells in the presence of bone marrow stromal cells (BMSCs) or with the supplement of recombinant EGF. SP MM cells were resistant to chemotherapeutics melphalan or bortezomib. Drug treatment stimulated SP-genesis. Mechanistically, EGFR, primed with EGF, activated the Hedgehog pathway and promoted the SP ratio; meanwhile, ALCAM inhibited EGFR downstream pro-MM cell signaling. Further, SP MM cells exhibited an increased number of mitochondria compared to the main population. Interference of the mitochondria function strongly inhibited SP-genesis. Animal studies showed that combination therapy with both an anti-MM agent and EGFR inhibitor gefitinib achieved prolonged MM-bearing mice survival. Hence, our work identifies ALCAM as a novel negative regulator of MM drug-resistance, and EGFR inhibitors may be used to improve MM therapeutic efficacy.

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