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A novel CBL-Bflox/flox mouse model allows tissue-selective fully conditional CBL/CBL-B double-knockout: CD4-Cre mediated CBL/CBL-B deletion occurs in both T-cells and hematopoietic stem cells. Oncotarget 2016 Aug 09;7(32):51107-51123

Date

06/09/2016

Pubmed ID

27276677

Pubmed Central ID

PMC5239462

DOI

10.18632/oncotarget.9812

Scopus ID

2-s2.0-84982282558   5 Citations

Abstract

CBL-family ubiquitin ligases are critical negative regulators of tyrosine kinase signaling, with a clear redundancy between CBL and CBL-B evident in the immune cell and hematopoietic stem cell studies. Since CBL and CBL-B are negative regulators of immune cell activation, elimination of their function to boost immune cell activities could be beneficial in tumor immunotherapy. However, mutations of CBL are associated with human leukemias, pointing to tumor suppressor roles of CBL proteins; hence, it is critical to assess the tumor-intrinsic roles of CBL and CBL-B in cancers. This has not been possible since the only available whole-body CBL-B knockout mice exhibit constitutive tumor rejection. We engineered a new CBL-Bflox/flox mouse, combined this with an existing CBLflox/flox mouse to generate CBLflox/flox; CBL-Bflox/flox mice, and tested the tissue-specific concurrent deletion of CBL and CBL-B using the widely-used CD4-Cre transgenic allele to produce a T-cell-specific double knockout. Altered T-cell development, constitutive peripheral T-cell activation, and a lethal multi-organ immune infiltration phenotype largely resembling the previous Lck-Cre driven floxed-CBL deletion on a CBL-B knockout background establish the usefulness of the new model for tissue-specific CBL/CBL-B deletion. Unexpectedly, CD4-Cre-induced deletion in a small fraction of hematopoietic stem cells led to expansion of certain non-T-cell lineages, suggesting caution in the use of CD4-Cre for T-cell-restricted gene deletion. The establishment of a new model of concurrent tissue-selective CBL/CBL-B deletion should allow a clear assessment of the tumor-intrinsic roles of CBL/CBL-B in non-myeloid malignancies and help test the potential for CBL/CBL-B inactivation in immunotherapy of tumors.

Author List

Goetz B, An W, Mohapatra B, Zutshi N, Iseka F, Storck MD, Meza J, Sheinin Y, Band V, Band H

Author

Yuri M. Sheinin MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Animals
CD4 Antigens
CD4-Positive T-Lymphocytes
Cell Differentiation
Cells, Cultured
Gene Deletion
Hematologic Neoplasms
Hematopoietic Stem Cells
Integrases
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutagenesis, Site-Directed
Organ Specificity
Proto-Oncogene Proteins c-cbl