Introduction of Constitutivelly Active Akt in Primary CLL B-Cells Results in Upregulation of Mcl-1, Bcl-XL and Cyclin D3 and Promotes Leukemic Cell Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2805-2805
Author(s):  
Pablo Longo ◽  
Stefania Gobessi ◽  
Luca Laurenti ◽  
Simona Sica ◽  
Giuseppe Leone ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Survival ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Cyclin D3 ◽  
Leukemic Cells ◽  
Interleukin 4 ◽  
Antiapoptotic Proteins ◽  
Sustained Activation ◽  
Constitutively Active

Abstract The PI3K/Akt and Raf/MEK/ERK pathways are key regulators of various cellular responses, including proliferation, survival, differentiation, migration and malignant transformation. These pathways are activated in chronic lymphocytic leukemia B-cells by a number of survival or growth stimulatory signals, such as immobilized anti-IgM antibodies, interleukin-4, phorbol-ester, CXCL12, or stimulatory CpG oligonucleotides. Moreover, enhanced activation of Akt has been implicated in the pathogenesis of the CLL-like disorder that develops in mice transgenic for the TCL1 oncogene. To further delineate the relative contribution of the PI3K/Akt and Raf/MEK/ERK pathways in regulating leukemic cell growth and survival, we introduced constitutively active Akt or constitutively active MEK2 in primary CLL B-cells by nucleofection. Expression of constitutively active Akt consistently promoted survival, as evidenced by a higher percentage of Annexin V/PI negative cells after 48 hours in culture (median 52%) compared to samples transfected with control vector (median 31%). Immunoblot analysis of several important antiapoptotic proteins revealed that enforced activation of Akt upregulates Mcl-1 and Bcl-xL, whereas no changes were observed in the levels of Bcl-2. Expression of constitutively active Akt also induced an increase in size and granularity of the leukemic cells, indicating increased metabolic activity. These changes were associated with significant induction of cyclin D3, indicating that activation of Akt is required for both leukemic cell survival and cell cycle progression. In contrast, introduction of constitutively active MEK2 induced sustained activation of ERK, but showed only a modest increase in the percentage of viable CLL B-cells (median 36%) and no significant changes in the levels of any of the investigated antiapoptotic proteins. These experiments provide direct evidence that sustained activation of Akt promotes leukemic cell survival and upregulates Mcl-1, an antiapoptotic protein that has been associated with resistance to chemotherapy in patients with CLL.

The Akt/Mcl-1 Pathway Plays a Prominent Role in Mediating Pro-Survival Signals Derived from the B-Cell Receptor in Chronic Lymphocytic Leukemia B-Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 341-341
Author(s):  
Pablo G. Longo ◽  
Luca Laurenti ◽  
Stefania Gobessi ◽  
Simona Sica ◽  
Giuseppe Leone ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Igm Antibodies ◽  
B Cell Survival ◽  
Sustained Activation ◽  
Constitutively Active

Abstract Studies of the immunoglobulin variable region gene repertoire have provided compelling evidence that antigen-stimulation through the B-cell receptor (BCR) plays a crucial role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). In addition, previous studies from our lab have shown that CLL B-cells become more resistant to spontaneous and chemotherapy-induced apoptosis following sustained engagement of the BCR with immobilized anti-IgM antibodies, which mimic stimulation with membrane-bound antigens. Investigation of downstream signaling pathways revealed that sustained BCR engagement induces prolonged activation of the PI3K/Akt and MEK/ERK pathways, which are key regulators of survival and proliferation in various cell types. To further define the role of sustained activation of the Akt and ERK kinases in regulating CLL growth and survival, we transfected constitutively active mutants of Akt (myr.Akt) and MEK2 in primary leukemic cells and evaluated changes in the expression of relevant apoptosis- and cell-cycle regulatory proteins. Introduction of constitutively active MEK2 resulted in activation of ERK, but did not induce significant changes in the levels of most investigated proteins (Bcl-2, Bcl-xL, Bim, Bax or Mcl-1). The only exception was the inhibitor of apoptosis protein XIAP, which showed increased expression in most but not all experiments. In contrast, transfection of myr.Akt showed a consistent increase in the levels of the antiapoptotic protein Mcl-1, which ranged from 1.5 to more than 4-fold higher levels with respect to cells transfected with control vectors. Increased expression of Mcl-1 was observed in all experiments and paralleled the rise in Mcl-1 that occurred following stimulation of CLL B-cells with immobilized anti-IgM antibodies. The increase in Mcl-1 protein levels was entirely due to post-transcriptional mechanisms, since quantification by real-time PCR did not show an increase in Mcl-1 mRNA levels. Constitutively active Akt also upregulated Bcl-xL and XIAP, although this increase was lower than the increase in Mcl-1. In addition, CLL cells transfected with myr.Akt showed induction of cyclin D3 and an increase in cell size and viability, indicating that sustained activation of Akt is required for both leukemic cell survival and cell cycle progression. To determine the relative importance of Mcl-1, Bcl-xL and XIAP in CLL B-cell survival, we downregulated expression of these proteins in primary CLL B-cells by RNA interference. Surprisingly, downregulation of Bcl-xL and XIAP had no effect on CLL B-cell survival. In contrast, silencing of Mcl-1 induced rapid and potent apoptosis in all investigated cases and abrogated the prosurvival effect of stimulation with immobilized anti-IgM antibodies. Together, these data provide direct evidence that pro-survival BCR signaling in CLL B-cells is mediated, at least in part, through the Akt/Mcl-1 pathway. In addition, they suggest that Mcl-1 could be an attractive candidate for targeting, either with small molecule inhibitors or with pharmacological agents that interfere with BCR signals propagated by the Akt kinase.

The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 846-855 ◽  
Author(s):  
Pablo G. Longo ◽  
Luca Laurenti ◽  
Stefania Gobessi ◽  
Simona Sica ◽  
Giuseppe Leone ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Viability ◽  
B Cell ◽  
Cell Survival ◽  
Leukemic Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Antiapoptotic Proteins

Sustained engagement of the B-cell receptor (BCR) increases apoptosis resistance in chronic lymphocytic leukemia (CLL) B cells, whereas transient stimulation usually has an opposite effect. The antiapoptotic BCR signal has been associated with prolonged activation of the PI3K/Akt and MEK/ERK pathways, which are key regulators of survival and proliferation in various cell types. To further define the relative contribution of the Akt and ERK kinases in regulating CLL B-cell survival, we introduced constitutively active mutants of Akt and MEK in primary CLL B cells and evaluated changes in the expression of relevant pro- and antiapoptotic proteins. Sustained activation of Akt resulted in increased leukemic cell viability and increased expression of the antiapoptotic proteins Mcl-1, Bcl-xL, and X-linked inhibitor of apoptosis protein (XIAP), thus largely recapitulating the effects of sustained BCR stimulation. Constitutively active MEK2 also up-regulated XIAP, but did not show a significant impact on leukemic cell survival. Down-regulation of Mcl-1 by siRNA treatment induced rapid and potent apoptosis in CLL B cells and blocked the antiapoptotic effect of sustained BCR stimulation, whereas down-regulation of Bcl-xL and XIAP did not affect leukemic cell viability. These data demonstrate that Akt and Mcl-1 are major components of a survival pathway that can be activated in CLL B cells by antigen stimulation.

Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2973-2979 ◽  
Author(s):  
Anne J. Novak ◽  
Richard J. Bram ◽  
Neil E. Kay ◽  
Diane F. Jelinek
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocyte ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
B Lymphocyte Stimulator

B-cell chronic lymphocytic leukemia (B-CLL) is defined by the accumulation of CD5+ B cells in the periphery and bone marrow. This disease is not characterized by highly proliferative cells but rather by the presence of leukemic cells with significant resistance to apoptosis and, therefore, prolonged survival. B-lymphocyte stimulator (BLyS) is a newly identified tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis and it shares significant homology with another TNF superfamily member, APRIL. The striking effects of BLyS on normal B-cell maintenance and survival raises the possibility that it may be involved in pathogenesis and maintenance of hematologic malignancies, including B-CLL. In this study, we investigated the status of APRIL and BLyS expression, as well as their receptors, in this disease. All B-CLL patient cells studied expressed one or more of 3 known receptors for BLyS; however, the pattern of expression was variable. In addition, we demonstrate for the first time that B-CLL cells from a subset of patients aberrantly express BLyS and APRIL mRNA, whereas these molecules were not detectable in normal B cells. Furthermore, we provide in vitro evidence that BLyS protects B-CLL cells from apoptosis and enhances cell survival. Because these molecules are key regulators of B-cell homeostasis and tumor progression, leukemic cell autocrine expression of BLyS and APRIL may be playing an important role in the pathogenesis of this disease.

Chronic Lymphocytic Leukemia-Exosomes Switch Endothelial and Mesenchymal Stromal Cells into Cancer-Associated Fibroblasts to Sustain Leukemic Cell Survival

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2927-2927 ◽  
Author(s):  
Jerome Paggetti ◽  
Franziska Haderk ◽  
Martina Seiffert ◽  
Bassam Janji ◽  
Yeoun Jin Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Survival ◽  
B Lymphocytes ◽  
Stromal Cells ◽  
Leukemic Cell ◽  
Lymphoid Organs ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells

Abstract Chronic lymphocytic leukemia (CLL), the most common hematologic malignancy in Western countries, is mostly affecting the elderly over 65 year-old. CLL is characterized by the accumulation of mature but non-functional B lymphocytes of clonal origin in the blood and the primary lymphoid organs. CLL was previously considered as a relatively static disease resulting from the accumulation of apoptosis-resistant but quiescent B lymphocytes. However, recent studies using heavy water labeling indicated that CLL is in fact a very dynamic disease with alternation of proliferation phases and peripheral circulation. A focus on the trafficking of CLL cells in vivo has shown that leukemic cells circulate between the blood and the lymphoid organs but have a preference for the bone marrow. Recent next-generation sequencing of CLL cells indicated the presence of different genetic subclones. This intraclonal heterogeneity observed in CLL subpopulations may be in part determined by the interactions that leukemic cells entertain with their microenvironment when B cells migrate into the lymph nodes and the bone marrow. Indeed, tumor-stroma interactions are not only providing signals necessary for leukemic cells survival but may also influence the clonal architecture and evolution. One of these interactions involves CLL-derived exosomes. Here, we show that CLL-exosomes efficiently transfer nucleic acids, including functional microRNAs, and proteins, including MHC-Class II molecules and B-cell specific proteins, to bone marrow mesenchymal stem cells and endothelial cells. CLL-exosomes also activate signaling pathways, including PI3K and NF-κB pathways, in these stromal cells. As a consequence, gene expression is strongly modified indicating a switch towards a cancer-associated fibroblast phenotype. Functionally, exosome-stimulated stromal cells show a striking actin cytoskeleton remodeling characterized by the formation of stress fibers, and enhanced proliferation, motility and angiogenic properties. We also identified several proteins synthesized and secreted by stromal cells that promote leukemic cell adhesion and survival ex vivo. To confirm the involvement of CLL-exosomes in CLL pathology in vivo, MEC-1-eGFP cells were subcutaneously injected into immunocompromised NSG mice together with CLL-exosomes. We observed a significant increase in tumor size and a reduction in survival of exosome-treated animals. Flow cytometry analysis of selected organs indicated an enrichment in leukemic cells in the kidney, providing a potential explanation to the renal failures observed in CLL patients. In conclusion, the communication between CLL cells and stromal cells may be a critical factor influencing CLL progression by promoting leukemic cell survival. This study demonstrates the crucial role of exosomes as mediators of the communication between leukemic cells and their microenvironment. Exosomes could thus represent a suitable target for therapeutic intervention in CLL. Disclosures No relevant conflicts of interest to declare.

Role of Hematopoietic-Specific Protein 1 (HS1) in Apoptosis in B-Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2809-2809
Author(s):  
Livio Trentin ◽  
Antonella Contri ◽  
Anna Maria Brunati ◽  
Federica Frezzato ◽  
Martina Frasson ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Survival ◽  
B Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Cell Fractionation ◽  
Normal Peripheral Blood ◽  
Protein Levels ◽  
The Mean

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults and is characterized by the accumulation of clonal CD5+ B lymphocytes. Several protein kinase pathways have been claimed to be involved in the regulation of apoptosis and cell survival. We previously demonstrated that Src kinase Lyn is overexpressed at the protein level in leukemic cells as compared to normal B lymphocytes with substantial amount of the kinase anomalously present in the cytosol. Moreover, most of Lyn is constitutively active in resting leukemic cells and is poorly responsive to BCR engagement. The finding that B CLL cells contained cytosolic Lyn fraction and are defective in programmed cell death suggest that the tyrosine phosphorlation of specific cytosolic targets might account, at least in part, for cell resistance to apoptosis. The 75 KDa HS1 protein is one of the major substrate of Lyn kinase upon BCR cross-linking that plays a crucial role in BCR- induced apoptosis in the mouse B lymphoma cell line WEHI-231. A recent study demonstrates that most HS1 protein was constitutively phosphorylated in B CLL patients with poor prognosis whereas only a fraction was phosphorylated in patients with good prognoses. In the present study, the relative HS1 protein levels were measured by Western blot analysis in 50 CLL patients belonging to different clinical stages. The relative HS1 protein levels were compared with corresponding levels in normal peripheral blood and with Jurkat cells. For normal B cells, the mean ± SD for HS1: actin ratio was 0,88 ± 0,10. There was considerable variation in the levels of HS1/actin ratio in CLL cells, which ranged from 0,49 to 2,50. Thus, compared to normal B cells, 15 CLL patients had a HS1 level which fell within the mean ± 1SD HS1 levels for normal B cells, while 9 patients had lower levels and 26 patients had higher levels. When assessed by flow cytometry, HS1 expression was normally distributed among CLL cells in individual patients and the mean levels correlated with those obtained by Western blotting. A difference in the levels of HS1 was also observed between mutated and unmutated patients. Using confocal microscopy and subcellular cell fractionation, we observed that HS1 protein was abnormally distributed in malignant cells as compare with normal B cells: a 4–7% aliquot of HS1 was anomalously present in the nucleus of leukemic cells. When primary CLL cells were in vitro treated whith dexamethazone, cyclosporin A, chlorambucil, or fludarabine the HS1 levels decreased correlating with the sensitivity of these cells to undergo apoptosis. Using a polyclonal antiserum against HS1 a major cleavage product of the apparent molecular weight of 64 KDa and one minor product of approximately 46 Kda was detected in B CLL cells cultured for 24 hours whith drugs. These findings suggest that HS1 plays a pivotal role in the regulation of cell survival of leukemic B cells and suggest that HS1 might represent a target for the development of new drugs to be used in vivo in these patients.

Raf-1 Is Over Expressed in Chronic Lymphocytic Leukemia and Promotes Cell Survival by Phosphorylation of ERK and BAD

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3120-3120 ◽  
Author(s):  
Miao Wang ◽  
P.M. Kluin ◽  
Stefano Rosati ◽  
Marjan Luinge ◽  
Simon M. G. J. Daenen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Western Blot ◽  
Cell Survival ◽  
Cell Lines ◽  
Annexin V ◽  
Lymphocytic Leukemia ◽  
Cyclin D3 ◽  
Qrt Pcr ◽  
Mrna Ratio

Abstract Introduction: The serine threonine kinase Raf-1 plays a protective role in many cell types, but its expression and function in CLL cells has not been studied in detail. In the present study, we analyzed Raf-1 expression and tested the hypothesis that Raf-1 is critical for CLL cell survival. Materials and Methods: By using qRT-PCR and western blot, we compared the expression of Raf-1 of mRNA and protein levels in purified B cells from 45 CLL cases and CD38 negative B cells from 5 reactive tonsils. By western blot, we analyzed the activity of phospho-Raf-1 (ser338) and its downstream targets (phospho-ERK1/2, phospho-BAD) in 23 CLL cases and 4 CLL cell lines (JVM-3, MEC-1, MEC-2 and MO1043) before and after IgM stimulation. By immunoprecipitation, we analyzed if Raf-1 co-localizes with Bcl-2. We correlated the change in phosphorylation status (Raf-1, ERK and BAD) in response to IgM stimulation with the ZAP-70/SYK mRNA ratio, which was detected by qRT-PCR in purified B cells from CLL cases. After using specific inhibitors, including the Raf-1 inhibitor GW5074, the Raf-1 destabilizer Geldanamycin and Bcl-2 inhibitor YC137, we investigated apoptosis by Annexin V flowcytometry in CLL cases and CLL cell lines as well as cell cycle changes in the 4 cell lines by flowcytometry. Results: In comparison to normal resting (CD38 negative) B cells, there was a strongoverexpression of Raf-1 in CLL cells, both at at the mRNA and protein level. Using qRT-PCR there was an almost linear correlation between Raf-1 and Bcl-2 expression. Moreover, the phosphorylation status of Raf-1 and ERK in response to IgM stimulation strongly correlated with the ZAP-70/SYK mRNA ratio. Using immunoprecipitation and confocal miscroscopy we found colocalization of Raf-1 with Bcl-2, which might account for the observed constitutive activation of BAD in CLL cells. The Raf-1 inhibitor GW5074, Raf-1 destabilizer Geldanamycin and Bcl-2 inhibitor YC137 all led to p-Raf-1 inhibition as well as downregulation of p-ERK and p-BAD. Additionally, all three inhibitors downregulated cyclin D3 and cyclin E, which are important for G0/G1 transition. We also found that GW5074 induced apoptosis in CLL cell lines and primary cells of CLL cases. Conclusion/Discussion: In conclusion, our study identifies Raf-1 as a critical anti-apoptotic and cell cycle regulating kinase in CLL cells.

scholarly journals Leukemic cells from a chronic T-lymphocytic leukemia patient proliferated in response to both interleukin-2 and interleukin-4 without prior stimulation and produced interleukin-2 mRNA with stimulation

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1177-1181 ◽  
Author(s):  
H Umadome ◽  
T Uchiyama ◽  
R Onishi ◽  
T Hori ◽  
H Uchino ◽  
...  
Keyword(s):  
T Cell ◽  
Binding Sites ◽  
Binding Assay ◽  
Interleukin 2 ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Interleukin 4 ◽  
High Affinity ◽  
T Cell Growth Factor

Abstract Recently, interleukin-4 (IL-4) has been clarified as having T-cell growth factor activity; therefore, it becomes of interest whether IL-4, as well as interleukin-2 (IL-2), affects the proliferation of leukemic cells derived from mature T cells. In the present study, we describe a case of chronic T-lymphocytic leukemia (T-CLL) with monoclonal proliferation of human T-lymphotropic retrovirus (HTLV)-I or HTLV-II negative CD3(+)4(+)8(-) T cell expressing IL-2 receptors without stimulation. Radiolabeled IL-2 binding assay revealed 750 high-affinity and 6,750 low-affinity binding sites per cell. In accordance with the expression of high-affinity IL-2 receptors, the leukemic cells proliferated in response to exogenous IL-2 without prior stimulation. In addition, exogenous IL-4 also induced their proliferation. Moreover, IL-2 and IL-4 exerted a synergistic effect on the leukemic cell proliferation. Although the expression of IL-2 or IL-4 mRNA was not detected in fresh leukemic cells, the expression of IL-2 mRNA, but not IL-4 mRNA, was induced by phytohemagglutinin stimulation, and the leukemic cells proliferated. These findings suggest that not only IL-2, but also IL-4 are involved in the proliferation of leukemic cells of T- CLL.

scholarly journals Leukemic cells from a chronic T-lymphocytic leukemia patient proliferated in response to both interleukin-2 and interleukin-4 without prior stimulation and produced interleukin-2 mRNA with stimulation

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1177-1181
Author(s):  
H Umadome ◽  
T Uchiyama ◽  
R Onishi ◽  
T Hori ◽  
H Uchino ◽  
...  
Keyword(s):  
T Cell ◽  
Binding Sites ◽  
Binding Assay ◽  
Interleukin 2 ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Interleukin 4 ◽  
High Affinity ◽  
T Cell Growth Factor

Recently, interleukin-4 (IL-4) has been clarified as having T-cell growth factor activity; therefore, it becomes of interest whether IL-4, as well as interleukin-2 (IL-2), affects the proliferation of leukemic cells derived from mature T cells. In the present study, we describe a case of chronic T-lymphocytic leukemia (T-CLL) with monoclonal proliferation of human T-lymphotropic retrovirus (HTLV)-I or HTLV-II negative CD3(+)4(+)8(-) T cell expressing IL-2 receptors without stimulation. Radiolabeled IL-2 binding assay revealed 750 high-affinity and 6,750 low-affinity binding sites per cell. In accordance with the expression of high-affinity IL-2 receptors, the leukemic cells proliferated in response to exogenous IL-2 without prior stimulation. In addition, exogenous IL-4 also induced their proliferation. Moreover, IL-2 and IL-4 exerted a synergistic effect on the leukemic cell proliferation. Although the expression of IL-2 or IL-4 mRNA was not detected in fresh leukemic cells, the expression of IL-2 mRNA, but not IL-4 mRNA, was induced by phytohemagglutinin stimulation, and the leukemic cells proliferated. These findings suggest that not only IL-2, but also IL-4 are involved in the proliferation of leukemic cells of T- CLL.

CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1962-1969 ◽  
Author(s):  
Luisa Granziero ◽  
Paola Circosta ◽  
Cristina Scielzo ◽  
Elisa Frisaldi ◽  
Stefania Stella ◽  
...  
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Follicular Dendritic Cells ◽  
Growth And Survival ◽  
High Affinity Receptor ◽  
Activated T Lymphocytes ◽  
Affinity Receptor

Growth and survival of chronic B-cell tumors are favored by the malignant cell's capacity to respond to selected microenvironmental stimuli provided by nontumoral bystander cells. To investigate which mechanisms operate in these crosstalks and whether they are malignancy-related or reproduce the mechanisms used by normal B cells we have studied the expression and functional role of semaphorin CD100 (now called Sema4D) in chronic lymphocytic leukemia (CLL) cells and normal CD5+ B cells. We demonstrate here that (1) leukemic and normal CD5+ B lymphocytes uniformly express CD100; (2) the CD100 high-affinity receptor Plexin-B1 is expressed by bone marrow stromal cells, follicular dendritic cells, and activated T lymphocytes, and is thus available to CD100+ lymphocytes in different specific microenvironments; and (3) upon interaction between CD100 and Plexin-B1 both CLL and normal CD5+ B cells increase their proliferative activity and extend their life span. These findings establish that Plexin-B1 is an easily accessible receptor for CD100 within the immune system. The encounter of CD100+ leukemic cells with Plexin-B1 may promote the proliferation and survival of malignant cells. The crosstalk operated by the CD100/Plexin-B1 interaction is not malignancy related but reproduces a mechanism used by normal CD5+ B cells.

scholarly journals S-100 beta positive T cell leukemia

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1299-1303
Author(s):  
K Takahashi ◽  
Y Ohtsuki ◽  
H Sonobe ◽  
K Hayashi ◽  
S Nakamura ◽  
...  
Keyword(s):  
T Cell ◽  
Human Peripheral Blood ◽  
Leukemic Cell ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
S 100 ◽  
T Cell Phenotypes

We reported a peculiar case with T cell leukemia. The patient was a 34- year-old woman showing extensive splenomegaly and marked leukemic cell proliferation and running a rapid fatal clinical course. The leukemic cells were morphologically ordinary lymphocytes showing suppressor/cytotoxic(s/c) T cell phenotypes and containing S-100b protein. Southern blot analysis revealed rearrangement of the beta chain genes of the T cell receptor (TcR) of the leukemic cells. Because these phenotypic and morphologic features were identical with those of S-100 beta+T lymphocytes (S-100 beta +TL) in normal human peripheral blood, we regarded this case as S-100 beta +T cell leukemia. We discussed clinicopathological features of S-100 beta +T cell leukemia/lymphoma by assessing similar cases reported so far. S-100 beta +T cell leukemia/lymphoma is a new type of s/c T lymphocytic leukemia/lymphoma with aggressive features.

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