Cryptochrome-1 Gene Expression is a Reliable Prognostic Indicator in Egyptian Patients with Chronic Lymphocytic Leukemia: A Prospective Cohort Study

Abstract

Objective: Traditional prognostic factors have proved insufficient to account for heterogeneity in the clinical behavior of chronic lymphocytic leukemia (CLL). Cryptochrome-1 (CRY-1) is a circadian clock gene essential in maintaining the circadian rhythm and regulating cell proliferation. We evaluated CRY-1 gene expression in CLL and addressed its putative role as a prognostic indicator for the clinical course of CLL.

Materials and methods: A total of 100 CLL patients at diagnosis were studied for CRY-1 gene expression by real-time reverse-transcription polymerase chain reaction and were followed for assessment of time to first treatment (TFT).

Results: CRY-1 was expressed in 94% of the CLL patients at diagnosis. The median CRY-1 relative gene expression level (0.006) stratified patients into high and low expression groups. Forty of 100 (40%) CLL patients showed high CRY-1, 54/100 (54%) showed low CRY-1, and 6/100 (6%) had undetectable CRY-1 gene expression. High CRY-1 gene expression was concordant with CD38⁺, Zap-70⁺, and double CD38⁺Zap-70⁺ expression; unfavorable/intermediate cytogenetics; unmutated immunoglobulin heavy-chain variable-region gene; and diffuse marrow infiltration. The high CRY-1 gene expression patient group exhibited shorter TFT than the patients with low CRY-1 gene expression. A Cox proportional hazard regression model identified CRY-1 gene expression to be independently predictive for TFT.

Conclusion: CRY-1 is differentially expressed among CLL patients, stratifying them into low-risk and high-risk groups. CRY-1 gene expression could constitute a reliable prognostic indicator for CLL progression, complementing the role of standard well-established prognostic factors. CRY-1 gene expression could be employed as a prognostic indicator for disease progression during the initial prognostic work-up and follow-up for CLL patients.

Keywords: Chronic lymphocytic leukemia; Cryptochrome-1; Circadian genes; Time to first treatment; Prognosis; Real-time polymerase chain reaction; CD38; Zap-70.

Figure 1. Cryptochrome-1 gene expression in chronic lymphocytic leukemia patients at diagnosis: (A) all chronic lymphocytic leukemia patients, (B) low and high Cryptochrome-1 gene expression groups. CRY-1: Cryptochrome-1.

Figure 2. Kaplan-Meier curve showing the time to first treatment for chronic lymphocytic leukemia patients based on Cryptochrome-1 gene expression levels. CRY-1: Cryptochrome-1.