Skin mesenchymal niches maintain and protect AML-initiating stem cells

Area of Science:

• Hematology
• Oncology
• Dermatology
• Stem Cell Biology

Background:

• Leukemia cutis, or skin infiltration by leukemic cells, is a common extramedullary manifestation of acute myeloid leukemia (AML).
• This condition is associated with a poorer prognosis, yet its underlying pathogenesis and maintenance mechanisms are not well understood.

Purpose of the Study:

• To investigate the role of skin mesenchymal niches in the pathogenesis and maintenance of acute myeloid leukemia (AML).
• To characterize the protective mechanisms employed by skin mesenchymal progenitor cells (MPCs) against chemotherapy for AML-initiating stem cells (LSCs).

Main Methods:

• Utilized a transplantation-induced MLL-AF9 AML mouse model to study massive AML cell infiltration in the skin.
• Performed niche characterization to identify skin mesenchymal progenitor cells (MPCs) and their interaction with AML-initiating stem cells (LSCs).
• Investigated the role of Lama4 in skin MPCs and its effect on LSC proliferation, chemoresistance, and retention post-chemotherapy using Lama4 deletion models and cytarabine treatment.

Main Results:

• Massive AML cell infiltration was observed in the skin of the MLL-AF9 AML mouse model, with these cells capable of regenerating AML post-transplantation.
• Skin harbored mesenchymal progenitor cells (MPCs) phenotypically similar to bone marrow mesenchymal stem cells, which protected AML-initiating stem cells (LSCs) from chemotherapy partly through mitochondrial transfer.
• Lama4 deletion in skin MPCs enhanced AML LSC proliferation and chemoresistance, leading to increased retention of chemoresistant LSCs in Lama4-/- mouse skin after cytarabine treatment.

Conclusions:

• Skin mesenchymal niches play a significant, previously unrecognized role in maintaining and protecting AML LSCs during chemotherapy.
• The interaction between skin MPCs and LSCs, particularly involving Lama4, influences LSC survival and chemoresistance.
• These findings suggest that skin mesenchymal niches may contribute to AML relapse and warrant further investigation.