Tyrosine Phosphatases in Cancer

PTPROt

PTPROt is a receptor-type PTP that is expressed mainly in hematopoietic cells. It has been proposed to be a tumor suppressor in chronic lymphocytic leukemia (CLL) following studies by others that showed that its overexpression in cultured hematopoietic cell lines, including from CLL, reduced survival and proliferation of these cells, and that transgenic mice expressing PTPROt in B cells survived longer with the disease. PTPROt expression is also reduced in CLL cells from humans and from mouse models of this disease.

In order to determine the link between reduced expression of PTPROt and CLL and to provide a molecular mechanism for this link we eliminated expression of PTPROt in mice and induced CLL in them. We find that the role of PTPROt in development of CLL is tightly linked with its expression levels: induction of CLL in mice carrying one allele of PTPROt results in earlier detection of disease and reduced lifespan of the mice. In contrast, CLL develops more slowly in mice that lack both allelels of this PTP, and the mice survive longer. Molecularly, we have shown that loss of one or both alleles of PTPROt up-regulates expression of IL-10 by tumor cells and increases IL-10 signaling in them, a factor known to support survival of CLL cells. Loss of both PTPROt alleles induces a second and distinct molecular function: it inhibits B-cell receptor signaling and increases cell death by apoptosis and autophagy, countering the pro-tumor effects of IL-10. Critically, the B-cell receptor/cell death effect is evident only upon loss of both PTPROt alleles, providing a mechanism for the significant change in the CLL phenotype as one moves from loss of one allele of PTPROt to loss of both alleles. This finding can also explain why in CLL, PTPROt expression is often reduced by not eliminated: reduced expression would provide tumor cells with a selectiver advantage, while complete loss of PTPROt would not.

These studies have been published in Oncogene (2017).