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ALOX5

Official Full Name
arachidonate 5-lipoxygenase
Background
This gene encodes a member of the lipoxygenase gene family and plays a dual role in the synthesis of leukotrienes from arachidonic acid. The encoded protein, which is expressed specifically in bone marrow-derived cells, catalyzes the conversion of arachidonic acid to 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid, and further to the allylic epoxide 5(S)-trans-7,9-trans-11,14-cis-eicosatetrenoic acid (leukotriene A4). Leukotrienes are important mediators of a number of inflammatory and allergic conditions. Mutations in the promoter region of this gene lead to a diminished response to antileukotriene drugs used in the treatment of asthma and may also be associated with atherosclerosis and several cancers. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined.
Synonyms
ALOX5; arachidonate 5-lipoxygenase; 5 LOX; leukotriene A4 synthase; arachidonic acid 5-lipoxygenase; arachidonic 5-lipoxygenase alpha-10 isoform; arachidonic 5-lipoxygenase delta-13 isoform; arachidonic 5-lipoxygenase delta-p10 isoform; arachidonic 5-lipo; arachidonic 5-lipoxygenase delta-10-13 isoform; 5-LO; 5LPG; LOG5; 5-LOX; MGC163204

Arachidonate 5-lipoxygenase (Alox5) is widely expressed in tissue cells and is mainly expressed in neutrophils, mast cells, dendritic cells, B lymphocytes, monocytes,and macrophages. Alox5 is expressed in a small amount under physiological conditions, and is up-regulated in the presence of pathological conditions. It is associated with the occurrence and development of the disease. Alox5 plays a crucial role in mediating inflammation to maintain homeostasis, but certain allelic variants of ALOX5 may increase the risk of atherosclerosis and coronary heart disease (CHD).

Alox5 and Myeloid Leukemia

Myeloid leukemia is a group of malignant clonal diseases in which hematopoietic stem/progenitor cells are malignant and accompanied by differentiation. They are classified into acute myelocytic leukemia (AML) and chronic myelocytic leukemia (CML).

Leukemia stem cells (LSCs) are the starting cells of leukemia and the root cause of treatment failure. Studies have shown that only effective removal of LSCs can fundamentally cure leukemia. Therefore, it was found that identifying molecular markers of LSCs is of vital impotance. In recent years, it has been observed in the mouse myeloid leukemia model that the Alox5 gene plays an important role in the self-renewal, proliferation and differentiation of mouse myeloid LSCs. Alox5 also plays an important role in the proliferation and differentiation of myeloid leukemia cells. It is a key molecule that determine the malignant biological properties of LSCs.

Alox5 and CML

Lucas et al. divided 48 patients with chronic CML who were treated with imatinib for 12 months according to their efficacy into three groups: response group, non-responder group and acute change group. At the initial diagnosis, the expression levels of Alox5 mRNA and 5-LO protein in peripheral blood leukocytes and CD34 + cells were lower than those in healthy controls. After treatment with imatinib, the expression level was up-regulated of Alox5 mRNA and 5-LO protein other than the acute change group. The expression level of Alox5 mRNA was not significantly changed during the treatment of the acute change group. This result suggests that the level of Alox5 expression at the time of initial diagnosis does not predict the efficacy of imatinib.

Plasma LTB4 concentration is a manifestation of 5-LO function. After treatment with imatinib, plasma LTB4 levels increased in all three groups, with the greatest increase in the blast group. The researchers used imatinib to treat peripheral blood mononuclear cells in healthy controls and then tested LTB4 concentrations. It was found that there was no significant difference in LTB4 concentration between imatinib-treated or imatinib-free groups, suggesting the increase of LTB4 concentrations is related to the development of the disease, Instead of being caused by imatinib. In addition, LTB4 binds to leukotriene B4 receptor 1 (LTB4R1) and positively regulates the expression of Alox5 and 5-LO proteins. The researchers found that the expression levels of LTB4R1 mRNA and protein in peripheral blood mononuclear cells of CML patients were lower than those in healthy controls; LTB4R1 mRNA was up-regulated in the responding group and down-regulated in the blast group.

Alox5 Figure 1. Arachidonic acid metabolism pathway. (Lucas, et al. 2014)

There were studies using real-time fluorescent quantitative PCR to detect the expression of Alox5 in bone marrow samples from 87 patients with CML (64 patients in chronic phase and 23 patients in advanced phase). Compared with the control group (20 bone marrow specimens from patients with non-hematologic malignancies), there was no significant difference in Alox5 expression levels between the two groups. Moreover, it was not associated with disease progression. The expression of Alox5 in CML and its clinical significance require further validation of multicenter and clinical large samples.

Alox5 and AML

Studies in a model of chronic myeloid leukemia have shown that Alox5 inhibitors also inhibit Wnt signaling. This is not due to Alox5-mediated disruption of lipid signaling, but due to the catalytically active inactive Alox5 form. In view of the fact that cancer stem cell-like cells (CSC) mediate remission of AML, clearing CSC based on Alox5 inhibition may provide a new clinical approach for immediate assessment of AML patients.

DeKelver et al. transfected runt-related transcription factor 1 (RUNX1)-runt related transcription factor 1 translocated to 1 (RUNX1T1, also known as ETO9a) (RUNX1-RUNX1T1, also known as RE9a) with Alox5+/+ or Alox5-/- mouse bone marrow cells. The time of subculture of Alox5+/+ cells was 13 weeks; the cells of Alox5-/- group were 5 weeks and could produce a little Cell clones of CD11b+. Moreover, control cells which not transfected with RE9a were cultured for 3 weeks. The researchers speculate that Alox5-/- weakens the malignant proliferative potential of RE9a and promotes the self-renewal and differentiation of HSCs. The expression of Alox5, Alox12 and Alox15 mRNA was detected in AML-M (M0, M1 and M2 leukemia) and acute lymphoblastic leukemia (ALL) patients, with the highest abundance of Alox5 mRNA. At the same time, patients with elevated LTB4 were detected, but they had no effect on leukemia cell growth and apoptosis. The researchers speculated that leukemia cell-derived LTB4 enhances and prolongs inflammatory damage by regulating the bone marrow microenvironment and initiating a cytokine network. Thus, the clinical significance and mechanism of Alox5 in AML need further study.

References:

  1. Tsai, M. Y., Cao, J., Steffen, B. T., Weir, N. L., Rich, S. S., & Liang, S., et al. (2016). 5‐lipoxygenase gene variants are not associated with atherosclerosis or incident coronary heart disease in the multi‐ethnic study of atherosclerosis cohort. Journal of the American Heart Association Cardiovascular & Cerebrovascular Disease, 5(3), e002814.
  2. Lucas, C. M., Harris, R. J., Giannoudis, A., Mcdonald, E., & Clark, R. E. (2014). Low leukotriene b4 receptor 1 leads to alox5 downregulation at diagnosis of chronic myeloid leukemia. Haematologica, 99(11), 1710-5.
  3. Roos, J., Oancea, C., Heinssmann, M., Khan, D., Held, H., & Kahnt, A. S., et al. (2014). 5-lipoxygenase is a candidate target for therapeutic management of stem cell-like cells in acute myeloid leukemia. Cancer Research, 74(18), 5244.
  4. Dekelver, R. C., Lewin, B., Lam, K., Komeno, Y., Yan, M., & Rundle, C., et al. (2013). Cooperation between runx1-eto9a and novel transcriptional partner klf6 in upregulation of alox5 in acute myeloid leukemia. Plos Genetics, 9(10), e1003765.
  5. Hamad, A., Sahli, Z., El, S. M., Mouteirik, M., & Nasr, R. (2013). Emerging therapeutic strategies for targeting chronic myeloid leukemia stem cells. Stem Cells International, 2013, 724360.

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