Critical role of Lama4 for hematopoiesis regeneration and acute myeloid leukemia progression
(2022) In Blood 139(20). p.3040-3057- Abstract
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 α4 (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,... (More)
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 α4 (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.
(Less)
- author
- organization
- publishing date
- 2022-05-19
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Blood
- volume
- 139
- issue
- 20
- pages
- 18 pages
- publisher
- American Society of Hematology
- external identifiers
-
- pmid:34958665
- scopus:85130708050
- ISSN
- 0006-4971
- DOI
- 10.1182/blood.2021011510
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2022 American Society of Hematology
- id
- a870a72b-0a9d-49da-af08-53d04b267404
- date added to LUP
- 2022-08-25 16:01:45
- date last changed
- 2024-06-25 10:02:07
@article{a870a72b-0a9d-49da-af08-53d04b267404,
abstract = {{<p>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 α4 (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<sup>−/−</sup> mice. Upon AML exposure, Lama4<sup>−/−</sup> mesenchymal stem cells (MSCs) exhibited dramatic molecular alterations, including upregulation of inflammatory cytokines that favor AML growth. Lama4<sup>−/−</sup> 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<sup>−/−</sup> 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.</p>}},
author = {{Cai, Huan and Kondo, Makoto and Sandhow, Lakshmi and Xiao, Pingnan and Johansson, Anne Sofie and Sasaki, Takako and Zawacka-Pankau, Joanna and Tryggvason, Karl and Ungerstedt, Johanna and Walfridsson, Julian and Ekblom, Marja and Qian, Hong}},
issn = {{0006-4971}},
language = {{eng}},
month = {{05}},
number = {{20}},
pages = {{3040--3057}},
publisher = {{American Society of Hematology}},
series = {{Blood}},
title = {{Critical role of Lama4 for hematopoiesis regeneration and acute myeloid leukemia progression}},
url = {{http://dx.doi.org/10.1182/blood.2021011510}},
doi = {{10.1182/blood.2021011510}},
volume = {{139}},
year = {{2022}},
}