Disparate effects of Shb gene deficiency on disease characteristics in murine models of myeloid, B-cell, and T-cell leukemia

The Src homology-2 domain protein B is an adaptor protein operating downstream of tyrosine kinases. The Shb gene knockout has been found to accelerate p210 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced leukemia. In human myeloid leukemia were tumors with high Src homology-2 domain protein B mRNA content, tumors were, however, associated with decreased latency and myeloid leukemia exhibiting immune cell characteristics. Thus, the aim of this study was to investigate the effects of Shb knockout on the development of leukemia in three additional models, that is, colony stimulating factor 3 receptor-T618I–induced neutrophilic leukemia, p190 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced B-cell leukemia, and G12D-Kras-induced T-cell leukemia/thymic lymphoma. Wild-type or Shb knockout bone marrow cells expressing the oncogenes were transplanted to bone marrow–deficient recipients. Organs from moribund mice were collected and further analyzed. Shb knockout increased the development of CSF3RT618I-induced leukemia and increased the white blood cell count at the time of death. In the p190 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase B-cell model, Shb knockout reduced white blood cell counts without affecting latency, whereas in the G12D-Kras T-cell model, thymus size was increased without major effects on latency, suggesting that Shb knockout accelerates the development thymic lymphoma. Cytokine secretion plays a role in the progression of leukemia, and consequently Shb knockout bone marrows exhibited lower expression of granulocyte colony stimulating factor and interleukin 6 in the neutrophilic model and interleukin 7 and chemokine C-X-C motif ligand 12 (C-X-C motif chemokine 12) in the B-cell model. It is concluded that in experimental mouse models, the absence of the Shb gene exacerbates the disease in myeloid leukemia, whereas it alters the disease characteristics without affecting latency in B- and T-cell leukemia. The results suggest a role of Shb in modulating the disease characteristics depending on the oncogenic insult operating on hematopoietic cells. These findings help explain the outcome of human disease in relation to Src homology-2 domain protein B mRNA content.

[1]  H. Schaefer,et al.  Chronic neutrophilic leukaemia: 14 new cases of an uncommon myeloproliferative disease , 2002, Journal of clinical pathology.

[2]  George Q. Daley,et al.  The P190, P210, and P230 Forms of the BCR/ABL Oncogene Induce a Similar Chronic Myeloid Leukemia–like Syndrome in Mice but Have Different Lymphoid Leukemogenic Activity , 1999, The Journal of experimental medicine.

[3]  Mark M. Davis,et al.  T cell receptor antagonism interferes with MHC clustering and integrin patterning during immunological synapse formation , 2004, The Journal of cell biology.

[4]  Markus G. Manz,et al.  Emergency granulopoiesis , 2014, Nature Reviews Immunology.

[5]  M. Busslinger.  Transcriptional control of early B cell development. , 2004, Annual review of immunology.

[6]  F. Behm,et al.  Clinical and biologic hallmarks of the Philadelphia chromosome in childhood acute lymphoblastic leukemia. , 1987, Blood.

[7]  K. Komurov,et al.  Enhanced MAPK signaling is essential for CSF3R induced leukemia , 2016, Leukemia.

[8]  S. Fröhling,et al.  K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors. , 2008, Blood.

[9]  A. Cumano,et al.  Interleukin-7 is necessary to maintain the B cell potential in common lymphoid progenitors , 2005, The Journal of experimental medicine.

[10]  M. Bergo,et al.  Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice , 2014, Leukemia.

[11]  T. Lipp,et al.  Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. , 2002, Blood.

[12]  L. Samelson,et al.  LAT The ZAP-70 Tyrosine Kinase Substrate that Links T Cell Receptor to Cellular Activation , 1998, Cell.

[13]  C. Heldin,et al.  Platelet-derived growth factor-mediated signaling through the Shb adaptor protein: effects on cytoskeletal organization. , 2000, Experimental cell research.

[14]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

[15]  R. Mulligan,et al.  Consequences of Shb and c-Abl interactions for cell death in response to various stress stimuli. , 2007, Experimental cell research.

[16]  J. Tyner,et al.  CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia , 2013, Leukemia.

[17]  Jon C. Aster,et al.  Efficient and Rapid Induction of a Chronic Myelogenous Leukemia-Like Myeloproliferative Disease in Mice Receiving P210 bcr/abl-Transduced Bone Marrow , 1998 .

[18]  Michael G. Kharas,et al.  The Src homology-2 protein Shb modulates focal adhesion kinase signaling in a BCR-ABL myeloproliferative disorder causing accelerated progression of disease , 2014, Journal of Hematology & Oncology.

[19]  A. Rolink,et al.  Transcriptional networks in developing and mature B cells , 2005, Nature Reviews Immunology.

[20]  G. Daley,et al.  The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity. , 2013, Experimental cell research.

[21]  David M Kranz,et al.  Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. , 2003, Immunity.

[22]  L. Cavelier,et al.  Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia , 2017, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[23]  L. Claesson‐Welsh,et al.  The Adaptor Protein Shb Binds to Tyrosine 1175 in Vascular Endothelial Growth Factor (VEGF) Receptor-2 and Regulates VEGF-dependent Cellular Migration* , 2004, Journal of Biological Chemistry.

[24]  V. Kríz,et al.  Shb deficient mice display an augmented TH2 response in peripheral CD4+ T cells , 2011, BMC Immunology.

[25]  Angela G. Fleischman,et al.  Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. , 2013, The New England journal of medicine.

[26]  G. Qin,et al.  Progenitor cell mobilization and recruitment: SDF-1, CXCR4, α4-integrin, and c-kit. , 2012, Progress in molecular biology and translational science.

[27]  L. Cantley,et al.  Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins , 1998, Oncogene.

[28]  T. Matozaki,et al.  Protein tyrosine phosphatase SHP‐2: A proto‐oncogene product that promotes Ras activation , 2009, Cancer science.

[29]  F. E. Bertrand,et al.  JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis , 2004, Leukemia.

[30]  Angela G. Fleischman,et al.  The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. , 2013, Blood.

[31]  R. Germain.  T-cell development and the CD4–CD8 lineage decision , 2002, Nature Reviews Immunology.

[32]  M. Welsh,et al.  Absence of the adaptor protein Shb potentiates the T helper type 2 response in a mouse model of atopic dermatitis , 2014, Immunology.

[33]  David H. Williams,et al.  Phosphorylation of SLP-76 by the ZAP-70 Protein-tyrosine Kinase Is Required for T-cell Receptor Function* , 1996, The Journal of Biological Chemistry.

[34]  I. Bruns,et al.  PDGFRα and CD51 mark human Nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion , 2013, The Journal of experimental medicine.

[35]  D. Hossfeld.  E.S. Jaffe, N.L. Harris, H. Stein, J.W. Vardiman (eds). World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues , 2002 .

[36]  V. Kríz,et al.  The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and proliferation. , 2003, Current molecular medicine.

[37]  C. Turck,et al.  Molecular Cloning of SLP-76, a 76-kDa Tyrosine Phosphoprotein Associated with Grb2 in T Cells (*) , 1995, The Journal of Biological Chemistry.

[38]  M. Diccianni,et al.  Ras activation in normal white blood cells and childhood acute lymphoblastic leukemia. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[39]  T. Jacks,et al.  Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[40]  E. Passegué,et al.  Oncogenic Kras Initiates Leukemia in Hematopoietic Stem Cells , 2009, PLoS biology.

[41]  Mario Cazzola,et al.  The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. , 2016, Blood.

[42]  S. Corey,et al.  Requirement of Src Kinase Lyn for Induction of DNA Synthesis by Granulocyte Colony-stimulating Factor* , 1998, The Journal of Biological Chemistry.

[43]  Kiran C. Bobba,et al.  The genetic basis of early T-cell precursor acute lymphoblastic leukaemia , 2012, Nature.

[44]  H. Lodish,et al.  Oncogenic Kras-induced leukemogeneis: hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation. , 2009, Blood.

[45]  J. Kutok,et al.  Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. , 2004, The Journal of clinical investigation.

[46]  Eric O Long,et al.  Essential role of LAT in T cell development. , 1999, Immunity.