Bone marrow endothelial cell-derived interleukin-4 contributes to thrombocytopenia in acute myeloid leukemia.

Abstract:

:Normal hematopoiesis can be disrupted by the leukemic bone marrow microenvironment, which leads to cytopenia-associated symptoms including anemia, hemorrhage and infection. Thrombocytopenia is a major and sometimes fatal complication in patients with acute leukemia. However, the mechanisms underlying defective thrombopoiesis in leukemia have not been fully elucidated. In the steady state, platelets are continuously produced by megakaryocytes. Using an MLL-AF9-induced acute myeloid leukemia mouse model, we demonstrated a preserved number and proportion of megakaryocyte-primed hematopoietic stem cell subsets, but weakened megakaryocytic differentiation via both canonical and non-canonical routes. This primarily accounted for the dramatic reduction of megakaryocytic progenitors observed in acute myeloid leukemia bone marrow and a severe disruption of the maturation of megakaryocytes. Additionally, we discovered overproduction of interleukin-4 from bone marrow endothelial cells in acute myeloid leukemia and observed inhibitory effects of interleukin-4 throughout the process of megakaryopoiesis in vivo Furthermore, we observed that inhibition of interleukin-4 in combination with induction chemotherapy not only promoted recovery of platelet counts, but also prolonged the duration of remission in our acute myeloid leukemia mouse model. Our study elucidates a new link between interleukin-4 signaling and defective megakaryopoiesis in acute myeloid leukemia bone marrow, thereby offering a potential therapeutic target in acute myeloid leukemia.

journal_name

Haematologica

journal_title

Haematologica

authors

Gao A,Gong Y,Zhu C,Yang W,Li Q,Zhao M,Ma S,Li J,Hao S,Cheng H,Cheng T

doi

10.3324/haematol.2018.214593

subject

Has Abstract

pub_date

2019-10-01 00:00:00

pages

1950-1961

issue

10

eissn

0390-6078

issn

1592-8721

pii

haematol.2018.214593

journal_volume

104

pub_type

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