Increasing evidence suggests that leukemia cells take shelter in the bone marrow (BM) niche, where they hide from chemotherapy and continue to divide. As yet, how leukemia cells alter the BM niche to facilitate their growth and assist them in evading chemotherapy is unclear. In this study, we provide compelling evidences that acute myeloid leukemia (AML), through exosome secretion, transformed the BM niche to facilitate their own growth and suppress normal hematopoiesis.

Using AML xenograft and MLL-AF9 knock-in mouse model, we show that leukemia cells as well as AML-derived exosomes stimulate the growth of BM stromal progenitors and blocked the osteolineage development in our stromal compartment analysis. Histological analysis and micro-CT examination confirmed loss or thinning of the bone in both leukemia and leukemic exosome-treated animals. Expression of cell adhesion molecules (NCAM1, VCAM1, CD44, OPN & ICAM1) and factors important for angiogenesis (Angpt1, Angpt2 and VEGF) are upregulated, whereas genes important for HSC maintenance (CXCL12 and SCF), osteoblast (OCN, OSX, Notch3 and IGF1) and chondrocyte (ACAN, SOX9) development are suppressed.

While we observed increases in phenotypic LT-HSC in AML-derived exosomes treated mice, these mice show reduced multilineage reconstitution ability, increased cell cycle entry and higher sensitivity to myeloablative stress suggesting that HSCs from exosome-treated mice have lower stem cell activity than their counterparts from normal mice.In addition, leukemia-modified stroma cells exhibit marked reduction in ability to support normal HSCs. Pre-treatment of AML-derived exosome “prime” the animal for leukemia cell invasion and accelerate leukemia progression. Conversely,disruption of exosome secretion by targeting Rab27a in AML cells significantly delays leukemia progression. These data strongly support the notion that leukemia-modified niches favor leukemic cell proliferation and suppress normal hematopoiesis.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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