Skin mesenchymal niches maintain and protect AML-initiating stem cells

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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 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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Funding Information
  • Swedish Research Council (2019-01361, 2022-01228, 2018-02963)
  • Swedish Childhood Cancer Foundation (PR2015-0142, FoAss13/015, PR2017/0154, PR2020-0166)
  • Swedish Cancer Foundation (CAN2017/774, 19 0092 SIA, 20 1222PjF, CAN 2018/793)
  • Dr Åke Olsson Foundation
  • Radiumhemmets Forskningsfonder (151241, 171162, 191253)
  • Karolinska Institute Wallenberg Institute for Regenerative Medicine
  • Karolinska Institute (2-1293/2014, 2021-00480)
  • Stiftelsen Clas Groschinskys Minnesfond (ref:M16 50)
  • Cancer Research Karolinska Institute
  • Incyte Biosciences Nordic
  • Knut and Alice Wallenberg Foundation

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