Open AccessNUP98‐HOXA10hd fusion protein sustains multi‐lineage haematopoiesis of lineage‐committed progenitors in transplant setting
Author(s) -
Dong Yong,
Wang Kaitao,
Weng Qitong,
Wang Tongjie,
Zhou Peiqing,
Liu Xiaofei,
Geng Yang,
Liu Lijuan,
Wu Hongling,
Wang Jinyong,
Du Juan
Publication year - 2020
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12885
Subject(s) - haematopoiesis , progenitor cell , biology , bone marrow , myeloid , lineage (genetic) , stem cell , microbiology and biotechnology , population , immunology , context (archaeology) , cancer research , genetics , medicine , gene , paleontology , environmental health
Objectives Exploring approaches of extending the haematopoiesis time window of MPPs and lineage‐committed progenitors might produce promising therapeutic effects. NUP98‐HOXA10hd (NA) fusion protein can expand long‐term haematopoietic stem cells (HSCs) and promote engraftment competitiveness without causing obvious oncogenesis. Our objectives were to investigate the roles of NA fusion protein in MPP and downstream lineage‐committed progenitor context. Material and Methods 300 sorted MPPs (Lin − CD48 − c‐kit + Sca1 + CD135 + CD150 − ) were mixed with 5 × 10 5 total BM helper/competitor cells and injected into irradiated recipients. For secondary transplantation, 5 × 10 6 total BM cells from primary recipient mice were injected into lethally irradiated recipients. NA‐MPP recipient mice were sacrified for flow cytometric analysis of bone marrow progenitors at indicated time points. Sorted MPPs and myeloid progenitors were used for RNA‐seq library preparation. Results We showed that NA‐expressing MPPs achieved significantly longer multi‐lineage haematopoiesis (>44‐week) than natural MPPs (20‐week). NA upregulated essential genes regulating long‐term haematopoiesis, cell cycle, epigenetic regulation and responses to stress in MPPs. These molecular traits are associated with the earlier appearance of a Sca1 ‐ c‐kit + myeloid progenitor population, and more abundant cellularity of lineage‐committed progenitor as well as bone marrow nucleated cells. Further, the NA‐derived primary bone marrow cells, which lack NA‐LSK cells, successfully repopulated secondary multi‐lineage haematopoiesis over 20 weeks. Conclusions This study unveiled that NA fusion protein promotes MPP and lineage‐committed progenitor engraftment via extending long‐term multi‐lineage haematopoiesis.