Article

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

Bijender KumarDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USAMayra GarcíaDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USALihong WengDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USAXiaoman JungDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USAJodi MurakamiDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USAXingbin HuDepartment of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of ChinaTinisha McDonaldDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USAAlex W. H. LinDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USAAshish KumarDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USADavid DiGiustoDepartment of Pediatric Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USAAnthony S. SteinDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USAVinod PullarkatDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USASusanta HuiDepartment of Radiation Oncology, City of Hope, Duarte, CA, USANadia CarlessoDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USAYH KuoDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USARavi BhatiaDivision of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USAGuido MarcucciDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USAC. C. ChenDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA

2017en

ABI

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.

Identifiers

DOI: 10.1038/leu.2017.259

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Cited by 20 references

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