|
| Status |
Public on Dec 05, 2017 |
| Title |
A lineage of myelolymphoblastic innate cells unmasked by inactivation of mTOR complex 1 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Blockades in hematopoiesis deprive the host of vital blood cells and frequently cause leukemia. Here we show that inactivation of mTORC1 in hematopoietic stem cells by deletion of Raptor unmasked a cell type, hereby called myelolymphoblastic innate cell (MLIC) based on unique gene expression signature, cell surface markers, morphology and functions. The MLICs are CD11b(+)Gr-1(-)B7-H1(high)F4/80(low) and have morphology of lymphoblasts with active Ig loci but no gene rearrangement. Within weeks of Raptor deletion, the MLICs account for nearly 50% of bone marrow cells and are found throughout both the lymphoid and non-lymphoid organs. Nevertheless, the MLICs are not malignant as they undergo very limited proliferation in vivo. Importantly, the MLICs broadly express pattern-recognition receptors and produce large amounts of inflammatory cytokines in response to all TLR ligands tested, rendering the host highly susceptible to pathogen-associated molecular patterns. Our data suggest that hematopoietic cell-intrinsic mTORC1 prevents development of self-destructive innate immune attack by suppressing generation of MLICs.
|
| |
|
| Overall design |
Raptor F/F mice were crossed with Mx1-Cre mice for more than 2 generations to get Raptor F/F (Ctrl) and Raptor F/F, Mx1-Cre (cKO) mice. Sex-matched 6-8 weeks old Ctrl mice and cKO mice were treated with polyinosinic: polycytidylic acid (pIpC) every other day for consecutive 7 times by intra-peritoneal (i.p.) injection to induce Cre expression and Raptor deletion in mouse hematopoietic system. Raptor mice were sacrificed 2-3 weeks after the last injection of pIpC. Whole BM cells from Raptor Ctrl mice (n=3) and FACS-sorted CD11b(+)Gr-1(-) BM MLICs from Raptor cKO mice (n=3) were used for RNA isolation and subsequent cDNA libraries construction. mRNA profiles of Ctrl-WBM and cKO-MLIC were examined by RNA-sequencing, in triplicate, using Illumina HiSeq 2000.
|
| |
|
| Contributor(s) |
Tang F, Zhang P, Cui Y, Zhang L, Jiang T, Liu Y, Zheng P |
| Citation(s) |
29206103 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AG036690 |
mTOR, Inflammation and Senescence of Hematopoietic Stem Cells |
CHILDREN'S RESEARCH INSTITUTE |
Pan Zheng |
| R01 AI064350 |
Checkpoints in the cellular response to tissue injury |
CHILDREN'S RESEARCH INSTITUTE |
Pan Zheng |
| R01 CA171972 |
Targeted Elimination of Cancer Stem Cells for AML Therapy |
CHILDREN'S RESEARCH INSTITUTE |
Yang Liu |
| U01 CA183030 |
Therapeutic Elimination of Stem Cells for Relapsed Pediatric AML |
CHILDREN'S RESEARCH INSTITUTE |
Yang Liu |
|
| |
| Submission date |
Apr 14, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Yang Liu |
| E-mail(s) |
YaLiu@childrensnational.org
|
| Phone |
202-476-5849
|
| Organization name |
Childrens' National Medical Center
|
| Department |
Center for Cancer and Immunology Research
|
| Lab |
Drs. Yang Liu and Pan Zheng's Lab
|
| Street address |
111 Michigan Ave NW
|
| City |
Washington |
| State/province |
DC |
| ZIP/Postal code |
20010 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
|
| Samples (6)
|
|
| Relations |
| BioProject |
PRJNA281089 |
| SRA |
SRP057155 |
Less...
More...