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- Title
IL-6 blockade reverses bone marrow failure induced by human acute myeloid leukemia.
- Authors
Zhang, Tian Yi; Dutta, Ritika; Benard, Brooks; Zhao, Feifei; Yin, Raymond; Majeti, Ravindra
- Abstract
Sometimes, crowding is not the problem: Bone marrow failure is a common and potentially deadly consequence of acute myeloid leukemia. Although traditional thinking holds that this bone marrow failure results from overcrowding, increasing evidence shows that it occurs even with low burden of disease that would not fill the bone marrow. Zhang et al. developed a mouse model that mimics the course of human disease and determined that acute myeloid leukemia cells produce a cytokine called interleukin-6, which interferes with red blood cell differentiation. In this mouse model, a blocking antibody targeting this cytokine treated the animals' anemia and improved their survival. Most patients with acute myeloid leukemia (AML) die from complications arising from cytopenias resulting from bone marrow (BM) failure. The common presumption among physicians is that AML-induced BM failure is primarily due to overcrowding, yet BM failure is observed even with low burden of disease. Here, we use large clinical datasets to show the lack of correlation between BM blast burden and degree of cytopenias at the time of diagnosis. We develop a splenectomized xenograft model to demonstrate that transplantation of human primary AML into immunocompromised mice recapitulates the human disease course by induction of BM failure via depletion of mouse hematopoietic stem and progenitor populations. Using unbiased approaches, we show that AML-elaborated IL-6 acts to block erythroid differentiation at the proerythroblast stage and that blocking antibodies against human IL-6 can improve AML-induced anemia and prolong overall survival, suggesting a potential therapeutic approach.
- Subjects
ACUTE myeloid leukemia; BONE marrow; ERYTHROCYTES; HEMATOPOIESIS; INTERLEUKIN-6; BONE marrow examination; CELL differentiation
- Publication
Science Translational Medicine, 2020, Vol 12, Issue 538, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aax5104