HO-1, RET and PML as possible markers for risk stratification of acute myelocytic leukemia and prognostic evaluation

Abstract

Abstract. Heme oxygenase-1 (HO-1) is an inducible isoform of HO that is activated in response to oxidative stress and has anti-apoptotic and pro-proliferative effects on leukemia cells. RET, a tyrosine kinase receptor; its expression levels are associated with the differentiation degree of acute myelocytic leukemia (AML) cells. The promyelocytic leukemia (PML) gene inhibits cell proliferation and tumor growth, participates in the differentiation of hematopoietic progenitor cells and induces cell apoptosis. However, the association between the expression levels of HO-1, RET and PML genes and the risk stratification of AML and prognosis have not previously been reported. In the present study, HO-1 was expressed in the human AML Kasumi-1, HL-60 and THP-1 cell lines, and HO-1 expression was regulated by Hemin (20 µmol/l) and ZnPPIX (10 µmol/l). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis demonstrated that expression of RET and PML were positively and negatively correlated with HO-1 expression, respectively. Bone marrow samples (18 favorable, 55 intermediate, 15 adverse and 2 unknown karyotype AML cases and 20 healthy donors) were collected from 90 randomly selected AML patients upon their first visit. The mRNA and protein expression of HO-1, RET and PML in samples was detected by RT-qPCR and western blot analysis. At the mRNA level, the adverse group expressed significantly higher levels of HO-1 and RET compared with the levels in the favorable and normal groups. The PML mRNA expression levels in adverse patient samples was lower compared with those of the intermediate group and favorable group. Western blot analysis demonstrated that the expression levels of HO-1, RET and PML proteins in all risk groups exhibited the same pattern of expression as was observed for the mRNA levels. The overall survival and relapse-free survival rates were shortest in AML patients with high HO-1 expression (Kaplan-Meier; log-rank, P<0.01). The results of the present study therefore indicate that HO-1, RET and PML may be critical in the risk-stratification and prognosis of AML. However, additional samples and clinical data should be collected and analyzed in order to provide stronger evidence for this hypothesis.

GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential

“…Increased RET activity, mediated through NRTN or ARTN ligand complexes secreted by stromal cells, is detected in 60–70% of Acute Myeloid Leukemia (AML) cases with myelomonocytic differentiation, where it may promote cell viability and proliferation through suppression of autophagy by mTORC1-mediated signals (Gattei et al, 1997, 1998; Camos et al, 2006; Rudat et al, 2018). Expression is higher in AML cases with worse prognosis (Yu et al, 2015). In patients with AML associated with a t(8;16)(p11;p13) translocation, increased RET expression may be a result of altered levels of a group of miRNAs predicted to regulate its normal expression (Diaz-Beya et al, 2013).…”

Heme Oxygenase-1 Has an Antitumor Role in Breast Cancer

“…Indeed, there is still a discussion as to whether HO-1 provides protection to the patient or to the tumor cells (11,36,37). In the majority of cancer types, HO-1 has been related to tumor progression, such as in colon cancer (6), gastric cancer (35,56), gliomas (18), liver cancer (55), pancreatic cancer (45), prostate cancer (1), head and neck cancer (17), lung cancer (9,12), thyroid cancer (66), bladder cancer (40,41), renal cancer (73), cholangiocarcinoma (29), melanomas (67), chronic myeloid leukemia (39), and acute myelocytic leukemia (72). Contrariwise, HO-1 has been reported to impair tumor progression in fewer types of cancer, such as colon cancer (3,4), hepatic cancer (75), prostate cancer (19), head and neck squamous cell carcinoma (71), and lung carcinoma (57).…”

Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo

“…RET is differentially expressed in human AML, with highest levels in leukemia with monocytic differentiation [ 44 ], which nicely fits to the acute myelomonocytic leukemia of our GEMM. Importantly, high RET expression in primary AML samples correlated with an adverse prognosis [ 45 ]. In contrast, Gfra transcripts were only rarely found in leukemic blasts, while they were—in the absence of RET—detected in BM-derived stromal cells [ 44 , 46 ].…”