Mice heterozygous for CREB binding protein are hypersensitive to γ-radiation and invariably develop myelodysplastic/myeloproliferative neoplasm

Abstract

Myelodysplastic syndrome (MDS) is a complex family of pre-leukemic diseases in which hematopoietic stem cell defects lead to abnormal differentiation in one or more blood lineages. Disease progression is associated with increasing genomic instability and a large proportion of patients go on to develop acute myeloid leukemia. Primarily a disease of the elderly, it can also develop following chemotherapy. We have previously reported that CREB binding protein (Crebbp) heterozygous mice have an increased incidence of hematological malignancies, and others have shown that CREBBP is one of the genes altered by chromosomal translocations found in patients suffering from therapy-related MDS. This led us to investigate whether hematopoietic tumor development in Crebbp+/- mice is preceded by a myelodysplastic phase and whether we could uncover molecular mechanisms that might contribute to its development. We report here that Crebbp+/- mice invariably develop myelodysplastic/myeloproliferative neoplasm within 9-12 months of age. They are also hypersensitive to ionizing radiation and show a marked decrease in PARP1 activity after irradiation. In addition, protein levels of XRCC1 and APEX1, key components of base excision repair machinery, are reduced in unirradiated Crebbp+/- cells or upon targeted knock down of CREBBP levels. Our results thus provide validation of a novel myelodysplastic/myeloproliferative neoplasm mouse model and, more importantly, point to defective repair of DNA damage as a contributing factor to the pathogenesis of this currently incurable disease.

Control of CREB expression in tumors: from molecular mechanisms and signal transduction pathways to therapeutic target

“…CREB overexpression was found in many solid tumor types like non-small lung carcinoma (NSCLC), glioblastoma, mammary carcinoma, melanoma and diffuse malignant mesothelioma when compared to adjacent normal tissues [8, 10, 14–22] as well as in hematopoietic malignancies [23–26]. This was accompanied by enhanced cell proliferation, reduced sensitivity to undergo apoptosis, increased angiogenesis and radiation-induced differentiation [27].…”

Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research

“…Naïve Crebbp 1/2 mice show HSC defects, 45 BM hypercellularity, splenomegaly, and myelodysplasia with hypersegmented granulocytes and pseudoPelger-Huet anomalies in the PB and abnormal megakaryocytes (ie, hyperlobulation and naked nuclei) in the BM. 30 There is no cytopenia. Instead, these mice show PB granulocytosis and excessive myelopoiesis in marrow and spleen.…”

“…Instead, these mice show PB granulocytosis and excessive myelopoiesis in marrow and spleen. 30 The hematologic syndrome observed in naïve Crebbp 1/2 mice was therefore classified as an MDS/MPN overlap disease. 40,42,46,47 The BM microenvironment contributes to the myeloproliferative component of the hematologic disease observed in Crebbp 1/2 mice, in part through the altered production levels of KITL and MMP9.…”

“…on May 9, 2018. by guest www.bloodjournal.org From cell count from a femoral flush, normalized for weight. 30 Mitotic figures, another measure of proliferation, represent ,1% of all BM cells in both humans and mice. 31 The cellular composition of mouse BM is distinct from humans in that it contains fewer granulocytes but more erythrocytes, monocytes, lymphocytes, and plasma cells.…”

Role of CREB Protein Family Members in Human Haematological Malignancies

“…Genomic instability is associated with progression of the disease so that a part of patients develops AML. It has been reported that an increased incidence of haematological malignancies occurs in CREBBP heterozygous mice and other authors have shown that CREBBP is one of the genes altered by chromosomal translocations in patients suffering from therapy-related myelodysplastic syndrome [69]. Moreover, it has been demonstrated that CREBBP(+/-) mice invariably develop myelodysplastic/myeloproli-ferative neoplasm within 9-12 months of age.…”