Critical role of Lama4 for hematopoiesis regeneration and acute myeloid leukemia progression

被引:21
作者
Cai, Huan [1 ]
Kondo, Makoto [1 ]
Sandhow, Lakshmi [1 ]
Xiao, Pingnan [1 ]
Johansson, Anne-Sofie [1 ]
Sasaki, Takako [2 ]
Zawacka-Pankau, Joanna [1 ]
Tryggvason, Karl [3 ]
Ungerstedt, Johanna [1 ]
Walfridsson, Julian [1 ]
Ekblom, Marja [4 ,5 ]
Qian, Hong [1 ]
机构
[1] Karolinska Inst, Karolinska Univ Hosp, Ctr Hematol & Regenerat Med HERM, Dept Med Huddinge, Stockholm, Sweden
[2] Oita Univ, Fac Med, Dept Matrix Med, Yufu, Oita, Japan
[3] Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden
[4] Lund Univ, Div Mol Hematol, Lund, Sweden
[5] Skane Univ Hosp, Dept Hematol, Lund, Sweden
基金
瑞典研究理事会;
关键词
MARROW VASCULAR NICHE; STEM-CELL NICHE; BONE-MARROW; MITOCHONDRIAL TRANSFER; MESENCHYMAL STEM; STROMAL CELLS; PROGENITOR CELLS; DISTINCT ROLES; TNF-ALPHA; LAMININS;
D O I
10.1182/blood.2021011510
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Impairment of normal hematopoiesis and leukemia progression are 2 well-linked processes during leukemia development and are controlled by the bone marrow (BM) niche. Extracellular matrix proteins, including laminin, are important BM niche components. However, their role in hematopoiesis regeneration and leukemia is unknown. Laminin a4 (Lama4), a major receptor-binding chain of several laminins, is altered in BM niches in mice with acute myeloid leukemia (AML). So far, the impact of Lama4 on leukemia progression remains unknown. We here report that Lama4 deletion in mice resulted in impaired hematopoiesis regeneration following irradiation-induced stress, which is accompanied by altered BM niche composition and inflammation. Importantly, in a transplantation-induced MLL-AF9 AML mouse model, we demonstrate accelerated AML progression and relapse in Lama4(-/-) mice. Upon AML exposure, Lama4(-/-) mesenchymal stem cells (MSCs) exhibited dramatic molecular alterations, including upregulation of inflammatory cytokines that favor AML growth. Lama4(-/-) MSCs displayed increased antioxidant activities and promoted AML stem cell proliferation and chemoresistance to cytarabine, which was accompanied by increased mitochondrial transfer from the MSCs to AML cells and reduced reactive oxygen species in AML cells in vitro. Similarly, we detected lower levels of reactive oxygen species in AML cells from Lama4(-/-) mice post-cytarabine treatment. Notably, LAMA4 inhibition or knockdown in human MSCs promoted human AML cell proliferation and chemoprotection. Together, our study for the first time demonstrates the critical role of Lama4 in impeding AML progression and chemoresistance. Targeting Lama4 signaling pathways may offer potential new therapeutic options for AML.
引用
收藏
页码:3040 / 3057
页数:18
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