Transcriptomics,Genomics

Dataset Information

164

SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms


ABSTRACT: 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. 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-/-

INSTRUMENT(S): Illumina HiSeq 2000 (Mus musculus)

SUBMITTER: Benjamin G. Neel  

PROVIDER: GSE99656 | GEO | 2017-06-06

SECONDARY ACCESSION(S): PRJNA389249

REPOSITORIES: GEO

altmetric image

Publications

SHP2 is required for BCR-ABL1-induced hematologic neoplasia.

Gu S S   Sayad A A   Chan G G   Yang W W   Lu Z Z   Virtanen C C   Van Etten R A RA   Neel B G BG  

Leukemia 20170814 1


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 leukemogenes  ...[more]

Similar Datasets

2016-01-17 | E-GEOD-75615 | ArrayExpress
2014-10-07 | E-GEOD-62121 | ArrayExpress
| EGAS00001001150 | EGA
2011-05-17 | E-GEOD-29347 | ArrayExpress
2012-07-05 | E-GEOD-36096 | ArrayExpress
| GSE42269 | GEO
2011-05-17 | GSE29347 | GEO
| GSE85744 | GEO
| PRJNA389249 | ENA
2010-07-15 | GSE21499 | GEO