Tuba Dogan Edgunlu, Volkan Karakus, Deniz Cetin, Gokhan Pektas

A study of the correlation between the serum Latexin levels and the mTORC subunits Raptor and Rictor in the molecular pathogenesis of chronic lymphocytic leukemia

Hematopoietic stem cells (HSCs) ensure the lifelong production of blood cells throughout a lifetime. Latexin (Lxn) is thought to have a tumor suppressor role and endogenously down-regulate the number of HSCs via increased apoptosis. Therewithal, Raptor, and Rictor are components of the mammalian target of rapamycin complex-1, and 2 (mTORC), which are the regulatory structures for cell growth. However, Lxn, Raptor, and Rictor-associated molecular mechanisms underlying leukemia-induced HSCs proliferation are largely unknown. Nowadays, chronic lymphocytic leukemia (CLL) remains the most common leukemia type in adults. Therefore, we investigated the serum levels of Lxn, Raptor, and Rictor in CLL patients. We randomized 40 patients with newly diagnosed, untreated CLL. Serum levels of Lxn, Raptor, and Rictor were examined using ELISA assay. The results showed that serum Lxn levels reduced in patients with CLL. Moreover, the Rictor level increased in association with the up-regulation of leukocytosis. Although there was a tendency for an increase of the Raptor levels, the differences did not reach statistical significance. The up-regulated Raptor and Rictor levels in CLL suggested that it was associated with cancer pathogenesis. However, decreased Lxn levels raised the question of whether the disease is secondary to epigenetic features or if it is caused by pathology related to Lxn. The negative correlation between Lxn and Raptor/Rictor levels can provide new methods for the treatment of CLL, which are likely to increase the quality of life and improve the prognosis of the disease. In conclusion, further clinical studies are needed to elucidate the role of Lxn and Raptor/Rictor with the newly defined molecular properties in hematological malignancies and the clinical implications of their use.

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Kikushige Y. Pathophysiology of chronic lymphocytic leukemia and human B1 cell development. Int J Hematol. 2020;111:634–41.
Swerdlow SH, Jaffe ES. International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer. 2008.
Riches JC, Ramsay AG, Gribben JG. Chronic lymphocytic leukemia: an update on biology and treatment. Curr Oncol Rep. 2011;13:379–85.
Fasolo A, Sessa C. Current and future directions in mammalian target of rapamycin inhibitors development. Expert Opin Investig Drugs. 2011;20:381–94.
Laplante M, Sabatini DM. Mtor signaling in growth control and disease. Cell. 2012;149:274–93.
Chappell WH, Steelman LS, Long JM, et al. Ras/raf/mek/erk and pi3k/pten/ akt/mtor inhibitors: Rationale and importance to inhibiting these pathways in human health. Oncotarget. 2011;2:135–64.
Kim LC, Cook RS, Chen J. Mtorc1 and mtorc2 in cancer and the tumor microenvironment. Oncogene. 2017;36:2191–201.
Dancey J. Mtor signaling and drug development in cancer. Nat Rev Clin Oncol. 2010;7:209–19.
Hales EC, Taub JW, Matherly LH. New insights into Notch1 regulation of the PI3K-AKT-mTOR1 signaling axis: targeted therapy of γ-secretase inhibitor resistant T-cell acute lymphoblastic leukemia. Cell Signal. 2014;26:149–61.
Zhang C, Liang Y. Latexin and hematopoiesis. Curr Opin Hematol. 2018;25:266–72.
Arimatsu Y. Latexin: a molecular marker for regional specification in the neocortex. Neurosci Res. 1994;20:131–5.
Uratani Y, Takiguchi-Hayashi K, Miyasaka N, et al. Latexin, a carboxypeptidase A inhibitor, is expressed in rat peritoneal mast cells and is associated with granular structures distinct from secretory granules and lysosomes. Biochem J. 2000;346:817–26.
Liu Y, Zhang C, Li Z, et al. Latexin inactivation enhances survival and long-term engraftment of hematopoietic stem cells and expands the entire hematopoietic system in mice. Stem Cell Reports. 2017;8:991–4.
Liu Y, Howard D, Rector K, et al. Latexin is down-regulated in hematopoietic malignancies and restoration of expression inhibits lymphoma growth. PLoS One. 2012;7:e44979.
Muthusamy V, Premi S, Soper C, et al. The hematopoietic stem cell regulatory gene latexin has tumor-suppressive properties in malignant melanoma. J Invest Dermatol. 2013;133:1827–33.
Ni QF, Tian Y, Kong LL, et al. Latexin exhibits tumor suppressor potential in hepatocellular carcinoma. Oncol Rep. 2014;31:1364–72.
Zhang H, Ren Y, Pang D, et al. Clinical implications of AGBL2 expression and its inhibitor latexin in breast cancer. World J Surg Oncol. 2014;12:142.
You Y, Wen R, Pathak R, et al. Latexin sensitizes leukemogenic cells to gamma-irradiation-induced cell-cycle arrest and cell death through Rps3 pathway. Cell Death Dis. 2014;5:e1493.
Xue Z, Zhou Y, Wang C, et al. Latexin exhibits tumor-suppressor potential in pancreatic ductal adenocarcinoma. Oncol Rep. 2016;35:50–8.
Ji B, Chen XQ, Misek DE, et al. Pancreatic gene expression during the initiation of acute pancreatitis: identification of EGR-1 as a key regulator. Physiol Genomics. 2003;14:59–72.
Bispo JAB, Pinheiro PS, Kobetz EK. Epidemiology and etiology of leukemia and lymphoma. Cold Spring Harb Perspect Med. 2019;pii:a034819.
Altieri A, Castro F, Bermejo JL, et al. Number of siblings and the risk of lymphoma, leukemia, and myeloma by histopathology. Cancer Epidemiol Biomarkers Prev. 2006;15:1281–86.
Beane-Freeman LE, Blair A, Lubin JH, et al. Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries: The National Cancer Institute cohort. J Natl Cancer Inst. 2009;101:751–61
Boice JD, Blettner M, Kleinerman RA, et al. Radiation dose and leukemia risk in patients treated for cancer of the cervix. J Natl Cancer Inst. 1987;79:1295–311.
Mauro FR, Gentile M, Foa R. Erythropoietin and chronic lymphocytic leukemia. Rev Clin Exp Hematol. 2002;1:21–31.
Mitsunaga K, Kikuchi J, Wada T, et al. Latexin regulates the abundance of multiple cellular proteins in hematopoietic stem cells. J Cell Physiol. 2012;227:1138–47.
Hosokawa K, Arai F, Yoshihara H, et al. Cadherin-based adhesion is a potential target for niche manipulation to protect hematopoietic stem cells in adult bone marrow. Cell Stem Cell. 2010;6:194–8.
Crane GM, Jeffery E, Morrison SJ. Adult haematopoietic stem cell niches. Nat Rev Immunol. 2017;17:573–90.
Abd-Elmageed ZY, Moroz K. Kandil E. Clinical signifcance of CD146 and latexin during diferent stages of thyroid cancer. Mol Cell Biochem. 2013;381:95–103.
Li Y, Basang Z, Ding H, et al. Latexin expression is downregulated in human gastric carcinomas and exhibits tumor suppressor potential. BMC Cancer. 2011;11:121.
Ouhtit A, Fernando A, Abd Elmageed Z, et al. CD146/Akt/NF-κB/latexin is a novel pathway involved in suppressing breast tumor growth. Breast. 2015;24:87–150.
Aoki M, Fujishita T. Oncogenic roles of the PI3K/AKT/mTOR axis. Curr Top Microbiol Immunol. 2017;407:153–89.
Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–45.
Memmott RM, Dennis PA. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal. 2009;21:656–64.