Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to improve and boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with hematologic malignancies???. A double edged sword
Authors: Elkazzaz Mahmoud Ramadan , Abo-Amer Yousry Esam-Eldin , Ahmed Amr , Haydara Tamer 
Published: November 2021

Abstract
The COVID-19 pandemic caused by SARS-CoV-2 has become a global health crisis. Patients with haematological malignancies (blood cancers) as B-cell chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency. In addition to impaired COVID-19 viral evolution and clearance was commonly seen in patients with haematological malignancies. Moreover, in patients with haematological malignancies, Covid-19 is associated with a mortality rate of 33-37%. As a result, patients with hematologic malignancies have been given priority for primary COVID-19 vaccination. After receiving COVID-19 vaccination, about one out of every four patients with blood cancer fails to produce detectable antibodies. Many studies have suggested that patients with haematological malignancies who have been fully vaccinated can develop severe and often fatal complications. COVID-19 is a virus that causes disease. A recent study by Oxford University scientists showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was significantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31. LZTFL1 gene is widely up regulated in respiratory epithelial cells, including ciliated epithelial cells, which have been found as one of the main cellular targets for COVID-19. The scientists in this study used a combined multiomics and machine learning approach and identified that the gain-of-function risk A allele of an SNP, rs17713054G>A, was a causative variant. With gene-expression analysis and chromosome conformation capture oxford scientists showed that the rs17713054-affected enhancer induces the interacting gene, LZTFL1. The rs17713054 A risk allele causes increased transcription by enhancing an epithelial–endothelial–fibroblast enhancer, which is aided by the addition of a second CEBPB binding motif. The risk allele generates a second CCAAT/enhancer binding protein beta (CEBPB) motif in the enhancer, according to sequence analysis.. As a result, the rs17713054 risk allele must generate a CCAAT/enhancer binding protein beta motif in order to increase covidm-19 risk by interacting with LZTFL1, according to this study. This study discovered that rs17713054 is an active enhancer of LZTFL1 in the lungs, which is linked to an increased risk of COVID-19, but not in immune cells, where CCR9 is expressed.. According to this study, LZTFL1 variants that increase the risk of severe COVID-19 disease are not found in immune cells. Here, we propose attestable hypothesis that the casual gene(LZTFL1) induced by all trans retinoic acid could be enhance the immune response in vaccinated patients with haematological malignancies SARS-CoV-2 mRNA vaccines have been shown to induce broad CD4+ T cell responses that recognize SARS-CoV-2 variants and HCoV-NL63. Fortunately, LZTFL1 has been discovered to potentially activate CD4 T cells and induce their immune response, as well as enhance IL-5 production under the control of all trans retinoic acid (ATRA). LZTFL1 expression is induced by ATRA in human primary CD4+ T cells. LZTFL1 has been found to be downregulated in a variety of cancers. TNM (tumour (T), node (N), and metastasis (M) stages of the tumour, as well as the number of metastasized lymph nodes, were found to have significant inverse correlations with loss of LZTFL1 expression (mLN). The T cell activation signal was further enhanced by overexpression of LZTFL1 in CD4+ T cells, as evidenced by increased NFAT activity. Furthermore, knocking down LZTFL1 reduced Th2 cytokine production, particularly IL-5 mRNA and protein, and suppressed ATRA-induced IL-5 production. In addition, retinoic acid is required for T cell migration in vitro and in vivo. Furthermore, trans retinoic acid was discovered to potentially downregulate EBP (CCAAT/enhancer binding protein beta motif) in the lungs, which could be used by the active enhancer rs17713054 of LZTFL1. Conclusions Haematological malignancies (blood cancers) patients are more vulnerable to COVID-19 disuse severity and mortality. Un fortunately mRNA vaccine seem to be less effective with weak immune response and insufficient level of generated antibodies in this category of patients. Therefore we suggest all trans retinoic acid is a good candidate as mRNA COVID-19 vaccine adjuvant via inducing LZTFL1 gene in CD4Tcells and this activation could improve the immune response and increase the level of the generated antibodies. Moreover LZTFL1 gene in CD4 T cells is not associated with increasing risk of COVID-19 infection because of absence of its enhancer(The risk allele of the SNP, rs17713054 A) in immune cells according to oxford recent study. In addition to all trans retinoic acid could inhibit CCAAT/enhancer binding protein beta motif that is generated by The risk allele of the SNP, rs17713054 A