B chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the elderly with heterogeneous clinical outcome. Rai stage, immunoglobulin heavy chain mutation status, Zap-70 expression, CD38 expression and chromosome abnormalities are used as prognostic markers. Among these, CD38, a differentiation marker of T lymphocytes, has been reported to have a role in B-CLL pathogenesis. High CD38 expression is associated with an unfavorable clinical course with advanced disease stage, poor responsiveness to therapy, short time to first treatment, and shorter survival, whereas B-CLL patients with low CD38 expression required minimal or no treatment, remained treatment free for longer time and had better survival. However, the molecular basis for the association of CD38 expression and clinical course of B-CLL patients is not known. Therefore, in this study we classified 35 B-CLL patients into CD38 high (>30%) and CD38 low (<30%) expressions, and the clinical course was correlated with gene expression profile using oligonucleotide DNA microarrays consisting 10,000 genes. There was a significant difference in CD38 expression levels in patients with good clinical outcome (mean CD38 ~ 20%) compared to poor clinical outcome (mean CD38 ~ 46%). Median time to treatment with high CD38 expression was 30 months compared to 69 months for low CD38 expressing patients. Significance analysis of microarray (SAM) identified 52 differentially expressed genes. From these genes, Hem1 and CTLA-4 were further studied because the Hem1 expression is limited to hematopoietic cells and CTLA-4 is involved in modulation of immune response. Also, CTLA-4 is a member of the immunoglobulin superfamily involved in the cell cycle regulation and prolongs the progression through the G1 phase of the cell cycle. The differential expression of Hem1 and CTLA-4 was also confirmed by semi-quantitative RT-PCR. Hem1 was found to be over expressed in B-CLL patients with higher CD38 expression compared to lower CD38 expression, whereas CTLA-4, was over expressed in B-CLL patients with lower CD38 expression compared to patients with high CD38 expression thus confirming the microarray results. Furthermore, to determine whether the expression levels of these two genes are associated with disease progression in B-CLL, log rank test was applied across the expression of Hem1 and CTLA-4 and disease progression. The higher expression of Hem1 was associated with shorter time to treatment (Figure 1), whereas lower expression of CTLA-4 was associated with shorter time to treatment (Figure 2). Thus, these results while confirming the prognostic value of CD38 expression, demonstrate the possible molecular basis of CD38 mediated clinical course in B-CLL patients involving key genes such as Hem1 and CTLA-4.

Figure 1
Figure 1.
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Figure 2
Figure 2.
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Topics:
cd38, cytotoxic t-lymphocyte antigen 4, time-to-treatment, disease progression, antigens, differentiation, chromosomal disorder, chronic b-cell leukemias, chronic lymphocytic leukemia, dna microarrays, gene expression profiling

(This work was supported by Elsa U. Pardee Foundation, Midlands MI).

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2005, The American Society of Hematology
2005
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