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Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors.

Basso K, Liso A, Tiacci E, Benedetti R, Pulsoni A, Foa R, Di Raimondo F, Ambrosetti A, Califano A, Klein U, Dalla Favera R, Falini B - J. Exp. Med. (2004)

Bottom Line: Comparison with the gene expression profiles of purified normal B cell subpopulations, including germinal center (GC), pre-GC (naive), and post-GC (memory) B cells, shows that HCL cells are more related to memory cells, suggesting a derivation from this B cell population.Notably, when compared with memory cells, HCL cells displayed a remarkable conservation in proliferation, apoptosis, and DNA metabolism programs, whereas they appeared significantly altered in the expression of genes controlling cell adhesion and response to chemokines.Finally, these analyses have identified several genes that are specifically expressed in HCL and whose expression was confirmed at the protein level by immunocytochemical analysis of primary HCL cases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Hematology, Policlinico Monteluce, Perugia 06100, Italy.

ABSTRACT
Hairy cell leukemia (HCL) is a chronic B cell malignancy characterized by the diffuse infiltration of bone marrow and spleen by cells displaying a typical "hairy" morphology. However, the nature of the HCL phenotype and its relationship to normal B cells and to other lymphoma subtypes remains unclear. Using gene expression profiling, we show here that HCL displays a homogeneous pattern of gene expression, which is clearly distinct from that of other B cell non-Hodgkin lymphomas. Comparison with the gene expression profiles of purified normal B cell subpopulations, including germinal center (GC), pre-GC (naive), and post-GC (memory) B cells, shows that HCL cells are more related to memory cells, suggesting a derivation from this B cell population. Notably, when compared with memory cells, HCL cells displayed a remarkable conservation in proliferation, apoptosis, and DNA metabolism programs, whereas they appeared significantly altered in the expression of genes controlling cell adhesion and response to chemokines. Finally, these analyses have identified several genes that are specifically expressed in HCL and whose expression was confirmed at the protein level by immunocytochemical analysis of primary HCL cases. These results have biological implications relevant to the pathogenesis of this malignancy as well as clinical implications for its diagnosis and therapy.

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Unsupervised hierarchical clustering of gene expression profiles generated from HCL, non-Hodgkin lymphomas, and B-CLL. Unsupervised analysis was performed on 16 HCL samples obtained from 14 different patients as follows: 11 samples are BM biopsies (HCL BM biopsies) and 5 samples (HCL) are from different origins, including 3 samples of CD19+ purified cells from peripheral blood (for two of them, the BM biopsy is also depicted), 1 sample of mononucleated cells from peripheral blood, and 1 sample of spleen biopsy. The representative panel of B cell malignancies includes 6 cases of follicular lymphoma (FL), 4 cases of Burkitt lymphoma (BL), 16 cases of diffuse large B cell lymphoma (DLBCL), 10 cases of mantle cell lymphoma (MCL), and 10 cases of B cell chronic lymphocytic leukemia (B-CLL). The dendrograms are generated using a hierarchical clustering algorithm based on the average-linkage method. In the matrix, each column represents a sample and each row represents a gene. The color scale bar shows the relative gene expression changes normalized by the standard deviation (0 is the mean expression level of a given gene). (A) The 62 tumor samples (16 HCL, 6 FL, 4 BL, 16 DLBCL, 10 MCL, and 10 B-CLL) are clustered according to their expression of 382 genes. (bone marrow signature) Genes specifically associated to the BM biopsies. (B) The HCL BM biopsies are not included in this analysis. The samples are clustered according to their expression of 389 genes.
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fig1: Unsupervised hierarchical clustering of gene expression profiles generated from HCL, non-Hodgkin lymphomas, and B-CLL. Unsupervised analysis was performed on 16 HCL samples obtained from 14 different patients as follows: 11 samples are BM biopsies (HCL BM biopsies) and 5 samples (HCL) are from different origins, including 3 samples of CD19+ purified cells from peripheral blood (for two of them, the BM biopsy is also depicted), 1 sample of mononucleated cells from peripheral blood, and 1 sample of spleen biopsy. The representative panel of B cell malignancies includes 6 cases of follicular lymphoma (FL), 4 cases of Burkitt lymphoma (BL), 16 cases of diffuse large B cell lymphoma (DLBCL), 10 cases of mantle cell lymphoma (MCL), and 10 cases of B cell chronic lymphocytic leukemia (B-CLL). The dendrograms are generated using a hierarchical clustering algorithm based on the average-linkage method. In the matrix, each column represents a sample and each row represents a gene. The color scale bar shows the relative gene expression changes normalized by the standard deviation (0 is the mean expression level of a given gene). (A) The 62 tumor samples (16 HCL, 6 FL, 4 BL, 16 DLBCL, 10 MCL, and 10 B-CLL) are clustered according to their expression of 382 genes. (bone marrow signature) Genes specifically associated to the BM biopsies. (B) The HCL BM biopsies are not included in this analysis. The samples are clustered according to their expression of 389 genes.

Mentions: The dendrogram (see Fig. 1) is generated using a hierarchical clustering algorithm based on the average-linkage method (11, 12). Only genes displaying a ≥twofold average change in the expression level across the whole panel were chosen to generate the hierarchical clustering. The expression value of each selected gene is normalized to have a zero mean value and unit standard deviation. The distance between two individual samples is calculated by Pearson distance with the normalized expression values. To perform the supervised gene expression analysis (see Fig. 2 A–D, and Figs. 3 and 4), we used the Genes@Work software platform, which is a gene expression analysis tool based on the pattern discovery algorithm structural pattern localization analysis by sequential histograms (13, 14). The classification method used for the cell type classification (see Fig. 2 E) was described previously (9). In brief, the classifier is a scoring function based on the values of a set of genes (gene cluster), which are differentially expressed in two sets of cell types and, thus, can be used for cell type classification. The higher the score, the more likely it is that a cell type is related to the phenotype set.


Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors.

Basso K, Liso A, Tiacci E, Benedetti R, Pulsoni A, Foa R, Di Raimondo F, Ambrosetti A, Califano A, Klein U, Dalla Favera R, Falini B - J. Exp. Med. (2004)

Unsupervised hierarchical clustering of gene expression profiles generated from HCL, non-Hodgkin lymphomas, and B-CLL. Unsupervised analysis was performed on 16 HCL samples obtained from 14 different patients as follows: 11 samples are BM biopsies (HCL BM biopsies) and 5 samples (HCL) are from different origins, including 3 samples of CD19+ purified cells from peripheral blood (for two of them, the BM biopsy is also depicted), 1 sample of mononucleated cells from peripheral blood, and 1 sample of spleen biopsy. The representative panel of B cell malignancies includes 6 cases of follicular lymphoma (FL), 4 cases of Burkitt lymphoma (BL), 16 cases of diffuse large B cell lymphoma (DLBCL), 10 cases of mantle cell lymphoma (MCL), and 10 cases of B cell chronic lymphocytic leukemia (B-CLL). The dendrograms are generated using a hierarchical clustering algorithm based on the average-linkage method. In the matrix, each column represents a sample and each row represents a gene. The color scale bar shows the relative gene expression changes normalized by the standard deviation (0 is the mean expression level of a given gene). (A) The 62 tumor samples (16 HCL, 6 FL, 4 BL, 16 DLBCL, 10 MCL, and 10 B-CLL) are clustered according to their expression of 382 genes. (bone marrow signature) Genes specifically associated to the BM biopsies. (B) The HCL BM biopsies are not included in this analysis. The samples are clustered according to their expression of 389 genes.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1887727&req=5

fig1: Unsupervised hierarchical clustering of gene expression profiles generated from HCL, non-Hodgkin lymphomas, and B-CLL. Unsupervised analysis was performed on 16 HCL samples obtained from 14 different patients as follows: 11 samples are BM biopsies (HCL BM biopsies) and 5 samples (HCL) are from different origins, including 3 samples of CD19+ purified cells from peripheral blood (for two of them, the BM biopsy is also depicted), 1 sample of mononucleated cells from peripheral blood, and 1 sample of spleen biopsy. The representative panel of B cell malignancies includes 6 cases of follicular lymphoma (FL), 4 cases of Burkitt lymphoma (BL), 16 cases of diffuse large B cell lymphoma (DLBCL), 10 cases of mantle cell lymphoma (MCL), and 10 cases of B cell chronic lymphocytic leukemia (B-CLL). The dendrograms are generated using a hierarchical clustering algorithm based on the average-linkage method. In the matrix, each column represents a sample and each row represents a gene. The color scale bar shows the relative gene expression changes normalized by the standard deviation (0 is the mean expression level of a given gene). (A) The 62 tumor samples (16 HCL, 6 FL, 4 BL, 16 DLBCL, 10 MCL, and 10 B-CLL) are clustered according to their expression of 382 genes. (bone marrow signature) Genes specifically associated to the BM biopsies. (B) The HCL BM biopsies are not included in this analysis. The samples are clustered according to their expression of 389 genes.
Mentions: The dendrogram (see Fig. 1) is generated using a hierarchical clustering algorithm based on the average-linkage method (11, 12). Only genes displaying a ≥twofold average change in the expression level across the whole panel were chosen to generate the hierarchical clustering. The expression value of each selected gene is normalized to have a zero mean value and unit standard deviation. The distance between two individual samples is calculated by Pearson distance with the normalized expression values. To perform the supervised gene expression analysis (see Fig. 2 A–D, and Figs. 3 and 4), we used the Genes@Work software platform, which is a gene expression analysis tool based on the pattern discovery algorithm structural pattern localization analysis by sequential histograms (13, 14). The classification method used for the cell type classification (see Fig. 2 E) was described previously (9). In brief, the classifier is a scoring function based on the values of a set of genes (gene cluster), which are differentially expressed in two sets of cell types and, thus, can be used for cell type classification. The higher the score, the more likely it is that a cell type is related to the phenotype set.

Bottom Line: Comparison with the gene expression profiles of purified normal B cell subpopulations, including germinal center (GC), pre-GC (naive), and post-GC (memory) B cells, shows that HCL cells are more related to memory cells, suggesting a derivation from this B cell population.Notably, when compared with memory cells, HCL cells displayed a remarkable conservation in proliferation, apoptosis, and DNA metabolism programs, whereas they appeared significantly altered in the expression of genes controlling cell adhesion and response to chemokines.Finally, these analyses have identified several genes that are specifically expressed in HCL and whose expression was confirmed at the protein level by immunocytochemical analysis of primary HCL cases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Hematology, Policlinico Monteluce, Perugia 06100, Italy.

ABSTRACT
Hairy cell leukemia (HCL) is a chronic B cell malignancy characterized by the diffuse infiltration of bone marrow and spleen by cells displaying a typical "hairy" morphology. However, the nature of the HCL phenotype and its relationship to normal B cells and to other lymphoma subtypes remains unclear. Using gene expression profiling, we show here that HCL displays a homogeneous pattern of gene expression, which is clearly distinct from that of other B cell non-Hodgkin lymphomas. Comparison with the gene expression profiles of purified normal B cell subpopulations, including germinal center (GC), pre-GC (naive), and post-GC (memory) B cells, shows that HCL cells are more related to memory cells, suggesting a derivation from this B cell population. Notably, when compared with memory cells, HCL cells displayed a remarkable conservation in proliferation, apoptosis, and DNA metabolism programs, whereas they appeared significantly altered in the expression of genes controlling cell adhesion and response to chemokines. Finally, these analyses have identified several genes that are specifically expressed in HCL and whose expression was confirmed at the protein level by immunocytochemical analysis of primary HCL cases. These results have biological implications relevant to the pathogenesis of this malignancy as well as clinical implications for its diagnosis and therapy.

Show MeSH
Related in: MedlinePlus