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  • Original Article
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Transcriptional control and signal transduction, cell cycle

SHP2 is required for BCR-ABL1-induced hematologic neoplasia

Leukemia volume 32, pages 203–213 (2018)Cite this article

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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 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, are essential for BCR-ABL1+, but not WT, pre-B-cell proliferation. The mitogen-activated protein kinase kinase (MEK) / extracellular signal-regulated kinase (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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Acknowledgements

We thank the Princess Margaret Genomics Centre for RNA-seq, and the Sick Kids-UHN Flow Cytometry Facility for fluorescence-activated cell sorting. This work was supported by R35CA49152 to BGN, and NIH R01 CA090576 to RAVE. BGN was a Canada Research Chair, Tier 1, and work in his laboratory was partially supported by the Princess Margaret Cancer Foundation and a grant from the Ontario Ministry of Health and Long Term Care.

Author contributions

SG and BGN designed the experiments. SG, GC and WY performed the experiments. SG, AS, ZL and CV analyzed RNA-seq data. RAVE provided essential advice. SG and BGN wrote and all authors edited the manuscript.

Author information

Author notes

  1. S Gu

    Present address: 5Current address: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.,

  2. B G Neel

    Present address: 6Current address: Laura and Issac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY 10016, USA.,

Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    S Gu & B G Neel

  2. Princess Margaret Cancer Center, Toronto, Ontario, Canada

    S Gu, A Sayad, G Chan, Z Lu, C Virtanen & B G Neel

  3. Department of Orthopaedics, Brown University Alpert Medical School, Providence, RI, USA

    W Yang

  4. Division of Hematology/Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA

    R A Van Etten

Authors
  1. S Gu
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  2. A Sayad
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  3. G Chan
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  4. W Yang
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  5. Z Lu
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  6. C Virtanen
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  7. R A Van Etten
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  8. B G Neel
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Corresponding author

Correspondence to B G Neel.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Gu, S., Sayad, A., Chan, G. et al. SHP2 is required for BCR-ABL1-induced hematologic neoplasia. Leukemia 32, 203–213 (2018). https://doi.org/10.1038/leu.2017.250

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  • DOI: https://doi.org/10.1038/leu.2017.250

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