Deficiency of the E3 ubiquitin ligase Hoip impairs maintenance of adult hematopoiesis and progression of myeloid leukemia. Mus musculus

The linear ubiquitin chain assembly complex (LUBAC) regulates canonical NF- kB pathway and programmed cell death via formation of linear type ubiquitin chains. LUBAC is known to play a key role for fetal hematopoiesis, immune response, several solid tumors, and B-cell lymphoma. But its role for adult hematopoiesis and myeloid leukemia has remained unclear. In this study, we show the role of Hoip, which is catalytic subunit of LUBAC in adult hematopoiesis and myeloid leukemia by mainly using conditional knockout mice of Hoip. Hoip was essential for both maintenance of normal adult hematopoiesis and progression of myeloid leukemia via regulation of NF-kB pathway and prevention of apoptosis. But there were different dependency of Hoip between normal hematopoiesis and myeloid leukemia, because Hoip deletion did not increase apoptosis of nomal hematopoietic stem cells but dramatically increase apoptosis in leukemia stem cells. In addition, inhibition of Hoip by small chemical thiolutin resulted in transient inhibition of adult hematopoiesis, but the same dose administration prolonged survival of mouse model of acute myeloid leukemia. Taken together, these results suggest the existence of therapeutic window between normal hematopoiesis and myeloid leukemia, and Hoip is a candidate for a therapeutic target for myeloid leukemia.