Skin mesenchymal niches maintain and protect AML-initiating stem cells

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 mouse skin. These cells were retained in the skin post-chemotherapy and could regenerate AML post-transplantation. The niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs maintained and protected AML-initiating stem cells (LSCs) from chemotherapy in vitro possibly via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs were retained in Lama4−/- mouse skin post-cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining AML LSCs and protecting them during chemotherapy, meriting future exploration of their impact on AML relapse.Key pointsLeukemic cells infiltrated in skin are capable to generate AML post-transplantationMesenchymal progenitors in skin contribute to forming the niche for AML cellsSkin mesenchymal progenitors protect AML stem cells possibly by mitochondrial transferLama4 deletion in skin mesenchymal niche promotes AML cell proliferation and chemoresistance to cytarabine