Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion

Abstract

Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes ‘primed’ the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML-derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell-supporting factors (for example, CXCL12, KITL and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion.

Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche

“…Our studies in immunodeficient mice confirm the relative accumulation and quiescence of residual HSC previously observed [16,18,22,23], and reveal that AML-EV suppress protein synthesis in LT-HSC. Mechanistically, AML-EV transfer miR-1246 to LT-HSC to cause the translational suppression of the mTOR subunit Raptor, which in turn facilitates the hypo-phosphorylation of S6RP with ensuing deficits in protein synthesis.…”

“…Several prior studies of BM niche-conversion emphasize leukemia-induced alterations in stromal and vascular function [8,[13][14][15]. Cell-cell interactions also target the hematopoietic components in the BM and contribute to the functional suppression and displacement of the hematopoietic progenitors predominantly responsible for steady-state hematopoiesis [15][16][17][18][19][20].…”

Exosomes play roles in sequential processes of tumor metastasis

“…For instance, non‐cancer cells, such as adipocytes, could transfer matrix metalloproteinase (MMP)3 proteins via exosomes, which fused with tumor cells enhance their invasive ability by activating MMP9 . Acute myeloid leukemia blasts remodel the bone marrow niche into a leukemia‐growth‐permissive and normal‐hematopoiesis‐suppressive microenvironment via TDEs, thus promoting leukemic cell proliferation and survival, while suppressing normal hematopoiesis . Here, we highlight five different crucial events in primary tumor sites, hoping to define the specific roles of exosomes in the initiation of metastasis.…”

Metabolic underpinnings of leukemia pathology and treatment

“…The adaptations of LSCs enable these cells to outcompete HSCs and take control of the bone marrow niche. AML cells can transform the niche into a proleukemic environment by promoting osteogenic differentiation of mesenchymal stem cells or by secreting exosomes . Leukemic blasts can also reprogram surrounding adipocytes to upregulate lipase activity thereby providing substrates for FAO .…”

“…AML cells can transform the niche into a proleukemic environment by promoting osteogenic differentiation of mesenchymal stem cells 127 or by secreting exosomes. 128 Leukemic blasts can also reprogram surrounding adipocytes to upregulate lipase activity thereby providing substrates for FAO. 55 Adipocytes are also a source of proinflammatory cytokines, 129 some of which can alter the balance between normal and pathologic hematopoietic cell behavior.…”