Phospholipase C Acts as Tumor Suppressor in Mouse Model

Researcher have determined why a strain of mice genetically engineered to lack a gene linked to the onset of allergy is prone to develop blood cancers such as leukemia and lymphoma.

Investigators from the La Jolla Institute for Allergy & Immunology (CA, USA) were interested in clarifying the role of the enzyme phospholipase C (PLC), which generates diacylglycerol and inositol 1,4,5-trisphosphate, in the process that leads to allergic inflammation. Toward this end, they genetically engineered a line of mice that lacked the gene for PLC-beta 3.

The investigators were surprised to find that this line of mutant mice developed myeloproliferative disease, lymphoma, and other tumors. The mutant mice had increased numbers of hematopoietic stem cells with increased proliferation, survival and, in the case of blood stem cells, the generation of myeloid cells. These findings were published in the August 4, 2009, issue of the journal Cancer Cell.

Molecular analysis revealed that the PCL-beta 3 mice had increased expression of the STAT5 (Signal Transducers and Activators of Transcription) transcription factor. STAT 5 regulates growth, differentiation, and survival of mammary cells, hematopoietic cells, hematopoietic malignancies, and carcinogenesis. Constitutive activation of STAT 5, resulting from the absence of PCL-beta 3, contributed to tumor formation.

"We wanted to better understand the PLC-beta 3 enzyme's possible role as a signaling pathway in asthma and other allergic diseases, so we began working with mice genetically engineered not to have that enzyme,” explained senior author Dr. Toshiaki Kawakami, a member of the La Jolla Institute for Allergy & Immunology specializing in asthma and allergy research. "We noticed that these mice developed a strange phenotype--myeloproliferation and a variety of tumors including lymphomas and some carcinomas. In the absence of the PLC-beta 3 protein, STAT5 goes into a state of constant activation, causing the development of abnormal myeloid cells.”

Commented further on the study's findings, Dr. Kawakami continued, "Some Burkitt's lymphoma cells have very little PLC-beta 3 expression and have very high levels of STAT5 activity, which is similar to our findings in myeloproliferative disease. We also have done human cell testing in some other lymphomas and leukemias--including myeloid leukemia--indicating that these diseases also use this mechanism [low expression of PLC-beta 3 and high STAT5 activity]. We hope other researchers will be encouraged by our work, and that it will prompt not only further analysis of this mechanism's role in various diseases, but attempts to develop drugs that would augment PLC-beta 3 in target cells.”

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La Jolla Institute for Allergy & Immunology