Oncogene iASPP enhances self‐renewal of hematopoietic stem cells and facilitates their resistance to chemotherapy and irradiation

Abstract

iASPP is a member of the apoptosis-stimulating proteins of p53 (ASPP) family and negatively regulates the apoptotic function of p53. In a hematopoietic system, overexpression of iASPP results in blockage of apoptosis, which may play a role in regulating hematopoietic stem cell (HSC) numbers. To address this, we first analyzed the expression of iASPP in patients with acute leukemia (AL) and found it was highly expressed in patients with AL. We further established a transgenic mouse model in which human iASPP was specifically expressed in hematopoietic cells. Overexpression of iASPP led to an increase in the proportion of long-term HSCs, short-term HSCs, multipotent progenitors, and common myeloid progenitor. HSCs from iASPP transgenic mice had an advantage in long-term reconstitution potential. In addition, the hematopoietic cells from iASPP transgenic mice exhibited a significantly lower level of p53 dependent apoptosis. After irradiation damage, hematopoietic cells of iASPP transgenic mice had a higher level of γ-H2AX expression, which lasted for a longer time. These results provide the first evidence that the iASPP can increase HSC populations and reconstitution capacity. Interestingly, in response to cell damage stimuli, hematopoietic cells can be protected against apoptosis by iASPP; meanwhile these apoptosis-resistant cells would have more mutation accumulation, which might be the potential risk for malignant transformation.-Jia, Y., Peng, L., Rao, Q., Xing, H., Huai, L., Yu, P., Chen, Y., Wang, C., Wang, M., Mi, Y., Wang, J. Oncogene iASPP enhances self-renewal of hematopoietic stem cells and facilitates their resistance to chemotherapy and irradiation.

MicroRNA-140 regulates cell growth and invasion in pancreatic duct adenocarcinoma by targeting iASPP

“…Manually enhanced expression of Since the effect of certain miRNAs on carcinogenesis depends on their downstream targets [24,25], various predictive algorithms were used to calculate target sequences for miR-140 in order to clarify the corresponding reaction chains involved in the inhibition of PDAC's proliferation and metastasis by induction of miR-140. The iASPP oncogene was verified as an important downstream target of miR-140 because of its frequent overexpression in many types of cancer and serves as an essential modulator of cell replication, survival, and migration [26][27][28][29]. Overexpression of miR-140 could downregulate the protein level of iASPP, while knockdown of miR-140 could up-regulate the expression of iASPP.…”

iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling

“…Inhibition of iASPP was shown to improve the efficacy of chemotherapy in cancer treatment [10–13]. Epithelial–mesenchymal transition (EMT) plays a key role in facilitating cancer metastasis, and suppression of EMT leads to enhanced sensitivity to chemotherapy [14].…”

Aspp1 Preserves Hematopoietic Stem Cell Pool Integrity and Prevents Malignant Transformation

“…Furthermore, Aspp1 contributes to the removal of severely damaged cells from the HSC pool by the induction of apoptosis after severe DNA damage. This is reminiscent of the recent study of iAspp in HSCs and leukemia, which revealed that overexpression of iAspp results in blockage of apoptosis and an increase in the proportion of damaged HSPCs after irradiation (Jia et al, 2014). Thus, the balance among Aspp family members may be critical to the fine-tuned control of DNA damage accumulation in the HSC pool.…”