Leukemia & Lymphoma, June 2011; 52(S2): 69–71
Tumor markers in hairy cell leukemia
JOHN E. JANIK Metabolism Branch, National Cancer Institute, Bethesda, MD, USA
Abstract Despite the availability of highly effective therapies for hairy cell leukemia, including cladrabine, deoxycoformycin, and interferon a, a significant fraction of patients relapse. The use of flow cytometry, bone marrow examination for minimal residual disease, and peripheral blood counts provides details about the level of disease activity, but the optimal method for following patient response and risk for relapse has not been established. Flow cytometry provides accurate assessments of circulating malignant cell counts even at very low levels, but does not provide details on the extent of bone marrow involvement. Bone marrow involvement can be assessed by biopsy, but is a painful procedure, and the extent of involvement by hairy cell leukemia is not always uniform. Thus, a single biopsy may not identify active disease when it is present. Magnetic resonance imaging is being evaluated as a means for assessing total body burden of disease in the marrow and shows great promise. Tumor markers that can be measured in the serum provide a method for assessing total body disease burden. Cell surface proteins can be shed by tumor cells through proteolytic cleavage to release portions of their extracellular domains. These proteolytic degradation products can be measured in the serum and provide a tool to monitor disease burden and response to therapy. Three cell surface molecules expressed by the malignant hairy cells, CD25, CD22, and CD307, have been used to monitor disease activity and follow patients at risk for relapse. Serum tumor markers provide a reliable, inexpensive, and non-invasive means of following patients with hairy cell leukemia for response to treatment and relapse.
Keywords: CD25, CD22, CD307, serum soluble proteins
Proteolytic release is responsible for the generation of three soluble proteins used to follow disease burden in patients with hairy cell leukemia: soluble CD25, the a-chain of the interleukin 2 receptor, soluble CD22, and soluble CD307, also known as immu- noglobulin superfamily receptor translocation-asso- ciated 2 (IRTA2/FcRH5) [1–3]. In addition to proteolytic cleavage, soluble cytokine receptors or other cell surface proteins can be generated by other mechanisms and released into the serum [4]. These include release of glycosylinositol phospholipid (GPI)-linked proteins, release of full-length receptors in exosome-like vesicles, alternative splicing of messenger RNA transcripts, and transcription of distinct genes that encode soluble cytokine-binding proteins. Generation of serum soluble CD25 and CD22 is through proteolytic release from the cell surface, whereas alternative splicing of the CD307 gene generates the majority of the soluble CD307 measured in the serum of patients with hairy cell leukemia. A small fraction is released by proteolytic degradation [1].
CD25 is expressed at low levels on resting T cells
but its expression is markedly increased upon T cell activation, and it is also expressed on B cells and monocytes [5]. Its expression on malignant hemato- poietic cells was first identified in patients with malignancy induced by the human T-cell leukemia virus type 1, adult T cell leukemia/lymphoma, and subsequently identified on the malignant cells from patients with hairy cell leukemia, anaplastic large cell lymphoma, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, and Hodgkin lymphoma, where it has provided a target for therapeutic intervention. CD25 is a transmembrane protein that is released as a truncated form of the receptor, serum soluble interleukin 2 receptor (sIL2R), through proteolytic cleavage. The site of cleavage of CD25 is between a cysteine residue at position 192 and a leucine at 193, and the fact that there is significant homology (12 of 13 amino acids identical) between the human and murine sequences at the cleavage site suggests that a specific enzyme is involved in the process. The specific enzyme
Correspondence: John Janik, MD, Bristol-Myers Squibb, Route 206 and Province Line Rd., Lawrenceville, NJ 08543, USA. Tel: (609)252-5987. E-mail:
john.janik@bms.com
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.568651
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