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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 1  |  Page : 3-6

Tryptase: A novel prognostic biomarker in chronic myeloid leukemia


1 Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Department of Medical Oncology Hematology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission18-Apr-2020
Date of Acceptance30-Apr-2020
Date of Web Publication11-Jun-2020

Correspondence Address:
Dr. Manisha Naithani
Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ami.ami_41_20

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  Abstract 

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome. It is treated with tyrosine kinase inhibitor agents targeted against the breakpoint cluster region-Abelson murine leukemia 1 fusion transcript. Disease risk stratification at diagnosis of chronic-phase (CP) CML is done using Sokal, Hasford, and EUTOS scores which use basophilia as a major component. However, basophil counts can be both variable and inaccurate. The serum tryptase level is being studied as a novel biomarker which represents the total basophil compartment. Tryptase, deriving its name from trypsin-like activity commonly expressed by mast cells, and also by immature basophils of patients suffering from various myeloid and leukemic disorders, has a role in tumor proliferation. Patients with seemingly low-normal levels of basophils and raised tryptase levels progress further in disease despite treatment. There is a recent interest in the role of serum tryptase as a prognostic marker in CML-CP.

Keywords: Chronic myeloid leukemia, novel biomarker, prognostic marker, tryptase


How to cite this article:
Mathew A, Naithani M, Nath UK. Tryptase: A novel prognostic biomarker in chronic myeloid leukemia. Acta Med Int 2020;7:3-6

How to cite this URL:
Mathew A, Naithani M, Nath UK. Tryptase: A novel prognostic biomarker in chronic myeloid leukemia. Acta Med Int [serial online] 2020 [cited 2020 Sep 21];7:3-6. Available from: http://www.actamedicainternational.com/text.asp?2020/7/1/3/286422


  Introduction Top


Chronic myeloid leukemia (CML), the most common leukemia of adults, is a myeloproliferative neoplasm mostly characterized by the presence of Philadelphia chromosome,[1] which accounts for 30% of adult leukemia.[2] Currently, breakpoint cluster region-Abelson murine leukemia (BCR-ABL)-positive CML is treated with tyrosine kinase inhibitor (TKI) and prognosticated using clinical scores such as Sokal/EUTOS score.[3],[4] Tryptase, a 134 kDa serine protease expressed by mast cells, derives its name from its trypsin-like activity of cleaving peptides or protein substrates on the carboxyl end of lysine or arginine residues.[5] Tryptase, of α- and β-subtypes, is encoded on the short arm of chromosome 16.[6],[7]


  Tryptase Has a Pivotal Role in Cancer Proliferation Top


Ilaria Marech et al. elucidated that tryptase is released when the stem cell factor binds to tyrosine kinase C-KIT receptor on the mast cell surface, leading to cellular degranulation by activating proteinase-activated receptor-2 (PAR-2). This acts as an agonist of G-protein couple receptor super-family of the epithelial and endothelial cells, resulting in G-protein coupled transduction leading to phosphatidylinositol hydrolysis and elevation of Ca2+ in tumor cells leading to tumor cell angiogenesis and proliferation.[5],[8] This also causes the phosphorylation of mitogen-activated protein kinase/extracellular signal-related kinase and mitogen-activated protein kinase pathway.[5],[8]

Increased calcium levels lead to activation and increased secretion of cyclo-oxygenase-2 and prostaglandin E2 and activation of sodium hydrogen antiporter-3 regulator-1, which, through Erzin/protein kinase A mediation, regulates many transmembrane receptors, transporters, and other proteins, leading to cancer cell proliferation.[8] Tryptase activation of PAR-2 increases vascular endothelial growth factor expression on the endothelial cell surfaces, inducing angiogenesis [Figure 1].[5],[8]
Figure 1: Role of tryptase in tumor proliferation and angiogenesis[5],[8]

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  Tryptase in Chronic Myeloid Leukemia Top


Leukemia, characterized by abnormal leukocytosis, is subclassified into acute and chronic based on the percentage of peripheral blood/bone marrow blast cells.[1],[2] CML has immature cells of myeloid lineage rising levels of erythrocytes, megakaryocytes, and leukocytes. Identifying Philadelphia chromosome (reciprocal translocation of chromosome 9 [ABL-gene] to chromosome 21 [BCR-gene]) confirms diagnosis.[1] This translocation makes CML patients responsive to TKIs.[2],[3]


  Role of Tryptase in Chronic Myeloid Leukemia Top


CML disease risk stratification and prognostication are done at diagnosis using scores such as Sokal, Hasford, and EUTOS scores recommended by the European Leukemia Net. These risk scores rely on various factors, most importantly spleen size and percentage of the peripheral blood basophils as prognostic parameters.[4] However, scores can be misleading due to variations in basophil percentage and inaccuracies in the identification of mature basophils and basophil precursors on the peripheral blood film. As shown by Samorapoomphichit et al. tryptase expression was more in neoplastic immature basophils in comparison to normal mature basophils which showed <1% tryptase secretion. Thus, tryptase is a promising marker of basophil compartment in CML as only immature basophils (which increase in CML) secrete tryptase.[9],[10] Raised tryptase levels in patients with hematological malignancies have been documented with a proven escalation of mRNA tryptase.[9],[11]


  Tryptase in Different Phases of Chronic Myeloid Leukemia Top


Tryptase levels are notably higher in advanced CML compared to CML-CP. With a study reporting that raised levels of serum tryptase (> 15 ng/ml), 70% were of patients in an advanced phase and 26% of CML-CP.[10] Conflictingly, Kelta et al. reported that higher mean ± standard deviation (SD) was found in CML-CP.[5]


  Tryptase as a Prognostic Marker in Chronic Myeloid Leukemia Top


Patients with higher tryptase levels had a higher risk of progression and development of events during their course of treatment, while a decrease in BCR-ABL transcripts was faster and deeper in patients with normal serum tryptase levels.[9],[10],[11] Ghalaut noticed that blast cell persistence was associated with elevated serum tryptase levels [Table 1].[12]
Table 1: Studies were done to identify the role of tryptase in Chronic Myeloid Leukemia

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Sperr et al. used serum tryptase replacing basophil count in the EUTOS score (spleen size × 4+ basophils × 7), renamed as EUTOS-T score (serum tryptase [ng/ml + 5 × spleen size). New score significantly differentiated patients of CML-CP as high risk (11.6%) and low risk (88.4%).[10] EUTOS-T scores were found to identify high-risk patients better than the EUTOS score.

Five-year survival rate was 84% and 0% in patients classified as low risk and high risk, respectively, according to the EUTOS-T score (P < 0.05). 11.5% of the patients from the low-risk group and 62.5% of patients from high-risk group had disease progression. 75% of high-risk patients and 21.3% of low-risk patients developed an event (death or progression) during the study. However, no significant differences were found in overall survival of the patients.[10],[11]


  Conclusion Top


Studies support the role of tryptase as a potential novel prognostic biomarker in CML. It has potential use as a more accurate estimation of the total basophil compartment, itself a prognostic marker in CML.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Druker JB, Marin D. Chronic myelogenous leukemia. In: Vincent DT, Theodore LS, Steven RA, editors. Cancer Principals and Practice of Oncology. Philadelphia: Wolters Kluwer; 2011. p. 10.  Back to cited text no. 1
    
2.
Alikia M, Gale RP, Apperly JF, Foroni L. Molecular techniques for personalized management of patients with CML. Biomol Detect Quantify 2017;11:4-20.  Back to cited text no. 2
    
3.
Garcia-Manero G, Faderal S, O'Brien S, Cortes J, Talpa M, Kantarjian MH. CML: A review & update therapeutic strategies. Cancer 2003;98:437-57.  Back to cited text no. 3
    
4.
Baccarani M, Deininger M, Rosti G. European Leukemia Net recommendations for the management of chronic myeloid leukemia. Blood 2013;122:872-84.  Back to cited text no. 4
    
5.
Kelta E, Ashall F, Abubeker A. Assessment of serum tryptase activity among acute and chronic myeloid leukemia patients visiting Hematology-Oncology Clinic at Tikuranbessa Specialized Hospital and comparison with healthy controls. Cancer Res J 2018;6:26-37.  Back to cited text no. 5
    
6.
Trivedi NN, Caughey GH. Human α-, β- and δ-tryptase. Handbook of Proteolytic Enzymes. 3rd ed. Philadelphia: Elsevier's; 2013. p. 2683-93.  Back to cited text no. 6
    
7.
Brahim SJ, Min HK, Fukuoka Y, Xia HZ, Schwartz BL. Expression of α-tryptase and β-tryptase by human basophils. J Allergy Clin Immunol 2004;113:1086-92.  Back to cited text no. 7
    
8.
Samorapoompichit P, Kiener HP, Schernthaner GH, Jordan JH, Agis H, Wimazal F, et al. Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms. Blood 2001;98:2580-3.  Back to cited text no. 8
    
9.
March I, Ammendola M, Gadaleta C, Zizzo N, Oakley C, Gadaleta CD, et al. Possible biological and translational significance of mast cell density in colorectal cancer. World J Gastroenterol 2014;20:8910-20.  Back to cited text no. 9
    
10.
Sperr WR, Pfeiffer T, Hoerman G, Heindihofer S, Sillaber C, Manhalter C, et al. Serum trypaste at diagnosis: A novel biomarker improving prognostication in Ph+chronic myeloid leukemia. Am J Cancer Res 2015;5:354-62.  Back to cited text no. 10
    
11.
Valent P, Sperr WR, Sotlar K, Reiter A, Akin C, Gotlib J, et al. The serum tryptase test: An emerging robust biomarker in clinical hematology. Expert Rev Hematol 2014;7:683-90.  Back to cited text no. 11
    
12.
Ghalaut PS. Tryptase as a Novel Marker for AML and CML Patients. Paper presented at: OMICS-Metabolomics & Systemic Biology. Philadelphia, US; 27-29 April, 2015.  Back to cited text no. 12
    


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Introduction
Tryptase Has a P...
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Role of Tryptase...
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