Inhibition of hypoxia inducible factor in B-ALL hypoxic microenvironment; a systematic review

Background and objective: Hematological malignancies have been considered as an important challenge meanwhile, there is no decisive consensus on current therapeutics approaches. B cell Acute Lymphoblastic Leukemia (B-ALL) is a characterized by uncontrolled proliferation of the B–lymphoid progenitor cells, in which, major remained challenges as resistance to therapy and tumor relapse, are problematic. These, encourage us to tumor microenvironment manipulation. The aim of this study is to investigate and evaluate of the hypoxic bone marrow microenvironment efficiency for tumor challenges solution. Search method: PubMed, ScienceDirect, Elsevier databases and Google Scholar search engine were searched from 2009 up to October with 5 keywords in English. 625 papers were found and according to our exclusion criteria and 316 articles were totally included in our study. Result: Hypoxia is a hallmark of the bone marrow microenvironment in hematological malignancies including B-ALL, which contributes to the proliferation of the leukemic cells and promotes the aggressiveness. The modulation of the hypoxic bone marrow microenvironment is performed by hypoxia inducible factor1-alpha (HIF1-alpha). HIF1-alpha regulates the expression of numerous immune related genes like: VEGF, CXCL12, Angiopoietin1, SLC2A1, Bim, Bax and BCL-2, leading to angiogenesis augmentation and malignant cells proliferation in B-ALL patients. It is demonstrated that several indirect HIF1-alpha inhibitors have been designed as: inhibitors of HIF1- alpha mRNA expression (2-methoxy-estradiol) and protein synthesis (Glyceollins), but there have been no direct HIF1-alpha inhibitors approved clinically.Conclusion: Despite great improvements in the treatment of B-ALL, relapse and recurrence is still of high importance. Immune system modifications present a variety of optimistic targeted therapeutics options. Further investigations on the more specific and direct HIF-alpha inhibition can open new insights into a more collaboration between clinical oncologists and basic molecular and cellular scientists, B-ALL considerations and recurrence rate diminution.