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| Status |
Public on Jun 06, 2017 |
| Title |
SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1+, but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.
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| Overall design |
RNA-Seq expression profiling of 16 mouse pre-B cell samples:
4 BCR-ABL/SHP2+/+
4 BCR-ABL/SHP2-/+
4 BCR-ABL/SHP2+/-
4 BCR-ABL/SHP2-/-
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| Contributor(s) |
Gu S, Sayad A |
| Citation(s) |
28804122 |
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| Submission date |
Jun 05, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Pamela Ohashi |
| E-mail(s) |
pam.ohashi@uhnresearch.ca
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| Organization name |
Princess Margaret Cancer Centre
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| Lab |
Ohashi Lab
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| Street address |
610 University Ave
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| City |
Toronto |
| State/province |
Ontario |
| ZIP/Postal code |
M5G 2C1 |
| Country |
Canada |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA389249 |
| SRA |
SRP108591 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE99656_ALL_FPKM.txt.gz |
1.0 Mb |
(ftp)(http) |
TXT |
| GSE99656_RAW.tar |
2.1 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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