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Skin mesenchymal niches maintain and protect AML-initiating stem cells

Sandhow, Lakshmi ; Cai, Huan ; Leonard, Elory ; Xiao, Pingnan ; Tomaipitinca, Luana ; Månsson, Alma ; Kondo, Makoto ; Sun, Xiaoyan ; Johansson, Anne Sofie and Tryggvason, Karl , et al. (2023) In Journal of Experimental Medicine 220(10).
Abstract

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC... (More)

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4−/− mouse skin after cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Experimental Medicine
volume
220
issue
10
article number
e20220953
publisher
Rockefeller University Press
external identifiers
  • pmid:37516911
  • scopus:85166001427
ISSN
0022-1007
DOI
10.1084/jem.20220953
language
English
LU publication?
yes
id
af59e467-5ed1-453f-ba92-3159e8ac678e
date added to LUP
2023-10-24 15:30:54
date last changed
2024-04-19 02:50:59
@article{af59e467-5ed1-453f-ba92-3159e8ac678e,
  abstract     = {{<p>Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4<sup>−/−</sup> mouse skin after cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.</p>}},
  author       = {{Sandhow, Lakshmi and Cai, Huan and Leonard, Elory and Xiao, Pingnan and Tomaipitinca, Luana and Månsson, Alma and Kondo, Makoto and Sun, Xiaoyan and Johansson, Anne Sofie and Tryggvason, Karl and Kasper, Maria and Järås, Marcus and Qian, Hong}},
  issn         = {{0022-1007}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{10}},
  publisher    = {{Rockefeller University Press}},
  series       = {{Journal of Experimental Medicine}},
  title        = {{Skin mesenchymal niches maintain and protect AML-initiating stem cells}},
  url          = {{http://dx.doi.org/10.1084/jem.20220953}},
  doi          = {{10.1084/jem.20220953}},
  volume       = {{220}},
  year         = {{2023}},
}