Brca1 and Tp53 co-deficiency causes a PARP-inhibitor sensitive erythroproliferative neoplasm.

Abstract

Mutations in the BRCA1 tumor suppressor gene, such as 5382insC (BRCA15382insC), give carriers an increased risk for breast, ovarian, prostate and pancreatic cancers. We have previously reported that, in mice, Brca1 deficiency in the hematopoietic system leads to pancytopenia and, as a result, early lethality. Here we explore the cellular consequences of Brca1 null and BRCA1 5382insC alleles in combination with Tp53 deficiency in the murine hematopoietic system. We find that Brca1 and Tp53 co-deficiency leads to a highly penetrant erythroproliferative disorder that is characterized by hepatosplenomegaly and expanded megakaryocyte erythroid progenitor (MEP) and immature erythroid blast populations. The expanded erythroid progenitor populations in both bone marrow and spleen have the capacity to transmit the disease into secondary mouse recipients, suggesting Brca1 and Tp53 co-deficiency provides a new murine model of hematopoietic neoplasia. This Brca1/Tp53 model replicates Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib sensitivity seen in existing Brca1/Tp53 breast cancer models and has the benefits of monitoring disease progression and drug responses via peripheral blood analyses without sacrificing experimental animals. In addition, this erythroid neoplasia develops much faster than murine breast cancer, allowing for increased efficiency of future preclinical studies.