Abstract
Huntingtin interacting protein 1 (HIP1) is an endocytic protein which is overexpressed in a variety of human cancers and involved in cancer-causing translocation in leukemia. However, the prognostic impact of HIP1 expression on AML remains unclear. In this study, quantification of HIP1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 270 AML patients. As a result, high HIP1 expression was seen more frequently in older patients, M4/M5 morphology and genes of NPM1 and DNMT3A mutations, and underrepresented in favorable karyotype subgroups and CEBPA double allele mutations in our AML patients. We also found high HIP1 expressers showed lower levels of hemoglobin. In addition, overexpression of HIP1 was associated with an inferior overall survival. The prognostic value of HIP1 expression was validated in patients from an independent TCGA cohort. Notably, up-regulation of miR-16, miR-15a, miR-28 and miR-660 were seen in high HIP1 expressers from the two independent cohorts. In vitro, interfereing of HIP1 expression by siRNA suppressed the proliferation of leukemic cells, and downregulation of these miRNAs were seen in THP-1 and Kasumi cell lines after silencing HIP1 expression. In conclusion, the HIP1 gene expression might serve as a reliable predictor for overall survival in AML patients.
Highlights
HIP1’s normal function, and accumulation of high levels of the free form of HIP15
Patients with high HIP1 expression were associated with a significantly higher frequency of NPM1 mutations (30% vs. 17%, P = 0.036) and DNMT3A mutations (13% vs. 5%, P = 0.031), a significantly lower frequency of favorable karyotype risk subgroup (2% vs. 9%, P = 0.037), CEBPA double allele mutations (7% vs. 24%, P < 0.001), compared with patients with low expression
We found distinct microRNA signatures associated with high HIP1 expression in Acute myeloid leukemia (AML)
Summary
HIP1’s normal function, and accumulation of high levels of the free form of HIP15. The true function of HIP1 remains unknown, it has been shown HIP1 protein has a role in the clathrin-mediated endocytosis which regulates several different signaling pathways, receptor trafficking and cytoskeleton dynamics[7]. It has previously reported alterations in HIP1 protein have been associated with tumors. In vitro analysis of the effects of HIP1 overexpression on cells indicated that it can transform fibroblasts[9]. These results suggest HIP1 acts as an oncogene in solid tumors. This study provides a reliable prognostic biomarker and critical drug target for AML patients
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