ADAM10 Overexpression Dysregulates S2/S3 Cleavage of Notch, Shifting Hematopoietic Lineage Commitment in Favor of Myelopoiesis (153.3)

Although the mechanism by which A Disintegrin and Metalloproteinase 10 (ADAM10) regulates hematopoiesis remains unclear, recent reports indicate its essential role in performing S2 cleavage of Notch receptors. Thus to determine the role of ADAM10 activity in hematopoiesis, we generated ADAM10 overexpressing mice (A10Tg). Transgene expression alters hematopoiesis post-hematopoietic Lineage-Sca-1+c-kit+ (LSK) subset differentiation but prior to lineage commitment of progenitor populations, which are dramatically affected in A10Tg mice. This results in delayed T cell development, abrogated B cell development, and expansion of myeloid derived suppressor cells (MDSCs). Albeit being in a tumor-free host, A10Tg MDSCs are functionally and phenotypically analogous to tumor-derived MDSCs. Given ADAM10’s role in Notch signaling, we hypothesized that the observed hematopoietic alterations may be a consequence of perturbed Notch signaling. In fact, blockade of ADAM10 (S2) rescues B cell development and reduces myeloid cells in A10Tg LSKs. Additionally, inhibition of γ-secretase (S3) in wild type LSKs results in enhanced myelopoiesis, mimicking the phenotype of A10Tg mice. Collectively, these findings indicate that the differential cleavage of Notch into S2 and S3 products regulated by ADAM10 is critical to hematopoietic cell-fate determination. Additionally, A10Tg mice provide a novel model for the examination of MDSC-mediated immune suppression in a tumor free environment.