Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia

Abstract

Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(−413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

“…As previously mentioned, the role of HO-1 in cancer is quite controversial since this enzyme can behave either as an anti-tumour factor or as a pro-tumour one [56,57,89]. HO-1 hyperactivation has been widely associated with tumour progression and acquired resistance to conventional chemotherapy [90][91][92]. Intriguingly, HO-1 cellular localization seems to drive different functions.…”

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

“…This polymorphism correlates with a reduced incidence of ischemic heart disease [ 58 ] and with graft survival after liver transplantation when present in the donor [ 59 ]. To our knowledge, only recently, the role of SNPs −413A > T in cancer risk has been analyzed by Bukowska [ 60 ]. The role of HO-1 polymorphisms in cancer will be discussed later.…”

“…So far, no association between SNP-413 and cancers has been demonstrated, as indicated by Wang et al, who analyzed studies conducted on digestive neoplasms [ 155 ]. Moreover, recently, no prognostic significance has been shown for (−413A > T) SNP in children with acute lymphoblastic leukemia (ALL) [ 60 ].…”

“…The chance to analyze HO-1 expression in cancer patients seems to be a useful tool to improve tumor diagnosis and to better define prognosis and therapy. On the one hand, the analysis of (GT)n length polymorphisms seems a very promising approach to assess the risk of treatment failure as recently proved in ALL patients carrier of short (GT) repeats [ 60 ]. On the other hand, the characterization of HO-1 expression in tumors may be a useful tool to improve tumor diagnosis and prognosis because it can correlate with tumor grade/stage, invasiveness, and clinical outcomes.…”

The role of heme oxygenase-1 in hematopoietic system and its microenvironment

“…HO-1 deficiency luckily seems to be extremely rare, but there are significant differences in HO-1 expression/activity in the human population due to the HMOX1 promoter polymorphism [ 58 , 59 ]. The differences in the number of GT repeats affect HO-1 expression: shorter alleles result in the higher basal expression and stronger induction by the HO-1 inducers than the longer alleles [ 60 ] and were linked to the risk of various diseases, such as diabetes [ 61 ], multiple sclerosis [ 62 ], chemotherapy-induced neutropenia [ 63 ] and cardiovascular diseases [ 64 , 65 ].…”