E2A Transcriptionally Regulates CD38 Expression In Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3599-3599
Author(s):  
Ifigenia Saborit-Villarroya ◽  
Tiziana Vaisitti ◽  
Davide Rossi ◽  
Giovanni D’Arena ◽  
Gianluca Gaidano ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Gene Transcription ◽  
De Novo ◽  
Regulatory Region ◽  
Surface Expression ◽  
Lymphocytic Leukemia ◽  
Cd38 Expression ◽  
De Novo Gene ◽  
E Box

Abstract Abstract 3599 CD38 is a cell surface molecule endowed with enzymatic and receptor functions. As an enzyme, CD38 is part of a large family of nucleotide-metabolizing ecto-enzymes (NMEs) involved in the catabolism of extra-cellular nucleotides. Its activity results in the dismantling of NAD and the generation of Ca2+ mobilizing compounds. CD38 also bind CD31, a non substrate ligand, expressed by endothelial and stromal cells. In the neoplastic context, CD38/CD31 interactions lead to increased proliferation, survival and chemotaxis. CD38 is a negative prognostic marker for chronic lymphocytic leukemia (CLL) patients and its expression is higher in BM than in peripheral blood cells. Furthermore, the exposure of CLL cells to specific combination of activatory signals (e.g., IL-2, IL-4, CD40L) results in an up-regulation of the molecule, that relies on de novo gene transcription. The human CD38 gene has a genetic single-nucleotide polymorphism (SNP), with a C→G variation in a putative E-box located in the regulatory region. E proteins have the ability to bind to E-box elements and to activate gene transcription. The frequency of the CD38 rare allele (G) has been recently reported to be higher in a subset of CLL patients characterized by clinical and molecular markers of poor prognosis. The aim of this work is to test whether CD38 is a target of E2A at least in CLL cells and if the SNP may affect CD38 gene transcription, influencing the binding affinity of the transcription factor. E2A expression was analyzed in a large cohort of CLL patients (n=72) and in normal B cells. Results indicate that the transcription factor was expressed by the majority of CLL samples, but at higher level in CD38+ ones. Moreover, it was absent in circulating B cells and splenocytes. A positive correlation between the presence of E2A in the nucleus and the surface expression of CD38 in G carrier patients was found. These results suggested that E2A is i) directly associated with CD38 expression and that ii) the binding of the transcription factor is influenced by CD38 genotype. Chromatin immunoprecipitation experiments indicated that E2A directly interacts with the CD38 regulatory region. Furthermore, the binding was stronger in the presence of the G allele. Silencing of E2A resulted in a significant reduction of CD38 surface expression, formally linking these two molecules and confirming the working hypothesis. A direct functional interplay between E2A and CD38 was obtained by mimicking in vitro conditions known to induce CD38 expression through de novo gene transcription. Exposure of CLL cells to TLR-9 ligands and IL-2, both inducers of CD38 expression, resulted in the up-regulation of the molecule. The effect was primarily conditioned by the presence of E2A and then by the G allele. The results obtained in the present work indicate that E2A and CD38 expression are functionally linked in a common pathway and the activity of E-protein is a necessary element for an efficient induction of CD38 transcription. Disclosures: No relevant conflicts of interest to declare.

Chronic Myelogenous Leukemia Diagnosed in the Setting of Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

2019 ◽  
Vol 28 (2) ◽  
pp. 216-224
Author(s):  
Kartik Viswanathan ◽  
Gail Roboz ◽  
Amy Chadburn ◽  
Susan Mathew
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Extra Chromosome ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Chromosome 8 ◽  
Myelogenous Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
Extensive Involvement

Chronic myeloid leukemia (CML) is rarely reported to occur in treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In this article, we report a woman in her 70s, diagnosed with CLL/SLL in 2000, untreated, who subsequently presented 12 years later with de novo CML, BCR-ABL1+. Her IGHV mutated CLL/SLL based on the initial sample in our laboratory showed homozygous and heterozygous 13q14.3 deletions, whereas her CML, at presentation, showed a 46,XX,t(9;22)(q34;q11.2)[7]/46,XX[18] karyotype with a p190 BCR-ABL1 transcript. The tumor burden of each clone varied with treatment, including when treated with dasatinib, used to target both clones. In addition, the cytogenetic abnormalities evolved over time and treatments and included acquisition of an extra chromosome 8 in the CML clone and a novel K1992T ATM missense mutation (47% allele frequency) in the CLL/SLL clone. The patient’s last bone marrow biopsy, 5 years after her CML diagnosis and 17 years after the CLL/SLL diagnosis, showed residual CML with extensive involvement by CLL/SLL (80%). Cytogenetic studies showed a 46,XX karyotype, while FISH identified 13q14.3 deletion and the BCR-ABL1 translocation in the CLL/SLL and CML clones, respectively. To date, this is the fourth case of concurrent CML, BCR-ABL1+ arising in untreated CLL/SLL. Here we show dynamic variation in the size of the 2 clonal processes reflecting the variable responsiveness to specific therapies. In addition to the unusual BCR-ABL1+ p190 transcript in the patient’s CML, a novel ATM K1992T mutation was identified in the CLL/SLL population.

scholarly journals Calcium-RasGRP2-Rap1 signaling mediates CD38-induced migration of chronic lymphocytic leukemia cells

2018 ◽  
Vol 2 (13) ◽  
pp. 1551-1561 ◽  
Author(s):  
Silvia Mele ◽  
Stephen Devereux ◽  
Andrea G. Pepper ◽  
Elvira Infante ◽  
Anne J. Ridley
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cd38 Expression ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Key Points ◽  
And Migration

Key Points Basal intracellular Ca2+ levels and migration increase with higher CD38 expression in CLL cells. Rap1 and the Rap1 guanine-nucleotide exchange factor RasGRP2 are required for CLL migration and regulated by CD38 levels.

scholarly journals Surface Expression of Bcl-2 in Chronic Lymphocytic Leukemia and Other B-Cell Leukemias and Lymphomas Without a Breakpoint t(14;18)

2008 ◽  
Vol 14 (9-10) ◽  
pp. 618-627 ◽  
Author(s):  
Brian A. McCarthy ◽  
Erin Boyle ◽  
Xue Ping Wang ◽  
Dorothy Guzowski ◽  
Santanu Paul ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Surface Expression ◽  
Lymphocytic Leukemia ◽  
Leukemias And Lymphomas

scholarly journals V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1410-1416 ◽  
Author(s):  
Alexander Kröber ◽  
Till Seiler ◽  
Axel Benner ◽  
Lars Bullinger ◽  
Elsbeth Brückle ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Expression Level ◽  
Chain Gene ◽  
P Value ◽  
Prognostic Impact ◽  
Survival Times ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Genomic Aberrations

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (VH) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed VH mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q−, +8q, 11q−, +12q, 13q−, t(14q), 17p−) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of VH mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (Pcor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% VH homology (95% confidence interval [CI], 96%-98% homology,Pcor <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, Pcor = .02). In univariate analyses, unmutated VH genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in theVH unmutated and VHmutated subgroups. High-risk genomic aberrations such as 17p− and 11q− occurred almost exclusively in the VHunmutated subgroup, whereas favorable aberrations such as 13q− and 13q− as single abnormalities were overrepresented in theVH mutated subgroup. In multivariate analysis, unmutated VH, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of VH mutation status and genomic aberrations to predict outcome in CLL.

Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1840-1847 ◽  
Author(s):  
Rajendra N. Damle ◽  
Tarun Wasil ◽  
Franco Fais ◽  
Fabio Ghiotto ◽  
Angelo Valetto ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Mutation ◽  
Lymphocytic Leukemia ◽  
Prognostic Indicators ◽  
Risk Category ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Staging Systems ◽  
V Genes ◽  
V Gene

Abstract Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (<30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

Different Expression of FcgammaRIIb in Chronic Lymphocytic Leukemia and Human Normal B Lymphocytes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3134-3134
Author(s):  
Carol Moreno ◽  
Rajendra Damle ◽  
Sonia Jansa ◽  
Gerardo Ferrer ◽  
Pau Abrisqueta ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocytes ◽  
Surface Membrane ◽  
Memory B Cells ◽  
Lymphocytic Leukemia ◽  
Cd38 Expression ◽  
B Cell Subsets

Abstract The Fcgamma receptors (FcγRs) are a family of molecules that modulate immune responses. FcγRIIb is an inhibitory FcγR that bears immunoreceptor tyrosine-based inhibitory motifs which transduce inhibitory signals on coligation with the surface membrane Ig of the B-cell antigen receptor (BCR). The role of FcγRIIb in controlling B cell activation through inhibition of BCR signaling has been extensively studied in animal models. Nevertheless, data on FcγRIIb are scant in human normal and neoplastic B cells, this being due to the lack of a specific antibody for human FcγRIIb. Consequently, there is little information on this receptor in chronic lymphocytic leukemia (CLL). Considering the activated nature of CLL cells and the central role of the BCR in the biology of the disease, studies of FcγRs are warranted. We used a novel specific mAb directly conjugated with Alexa 488 fluorophore that solely reacts with the human FcγRIIb (MacroGenics, Inc.) to investigate the receptors expression on CLL and normal human B cells. The study population included 84 patients with CLL and 24 age- and sex-matched controls. FcγRIIb expression was assessed as the mean fluorescence intensity (MFI) of surface membrane staining. In CLL cells, FcγRIIb was measured on CD19+CD5+ cells in combination with CD38, CD49d or CD69. Normal B cells were immunostained for CD19, CD5, IgD and CD38 expression and B cell subsets: naïve (IgD+CD38−), activated (IgD+CD38+) and memory B cells (IgD−CD38−) were studied for their relative expression of FcγRIIb. FcγRIIb expression was found significantly higher in naïve B cells compared to activated and memory B cells [median MFI: 17420 (11960–21180) vs. 11.140 (7899–16970) and 11.830 (6984–17100); p<0.001]. Significant differences were also observed between CD5− and CD5+ normal B cells. In contrast, FcγRIIb expression was lower in CLL cells than in CD5+ and CD5− normal B lymphocytes [median MFI: 6901(1034–42600), 10180 (5856–14820) and 12120 (7776–16040); p<0.05)]. Interestingly, FcγRIIb expression was variable within individual CLL clones, this being higher in CD38+ and CD49d+ cells than in CD38− and CD49d− cells (p<0.05). Furthermore, the highest density of FcγRIIb was observed on those cells which coexpressed CD38 and CD49d. In contrast, no significant differences were observed between FcγRIIb and the expression of the activation antigen CD69. Although CD69 and CD38 expression was significantly higher on unmutated IGHV cases, no correlation was found between FcγRIIb levels and IGHV mutational status. Similarly, there was no correlation between FcγRIIb and other poor prognostic variables such as ZAP-70 (≥20%), CD38 (≥ 30%) or high risk cytogenetics. Nevertheless, cases with ≥ 30% CD49d+ cells had higher FcγRIIb expression than those with <30% CD49d+ cells (p=0.006). The findings presented in this study suggest a hierarchy of FcγRIIb expression in normal B-cells, CLL cells and their subpopulations: circulating normal CD5− B cells > circulating normal CD5+ B cells > circulating CD5+ CLL B cells. In addition, although FcγRIIb is present on all normal B cell subsets its expression is higher in naïve B cells. Furthermore, in CLL FcγRIIb density is greater in CD38+ and CD49d+ cells within the clone. Although CD49d and FcγRIIb on CLL clones is linked in a direct manner, there is no relationship with FcγRIIb density and IGHV mutations, ZAP-70, CD38 and unfavorable cytogenetic markers. Finally, the relationship between FcγRIIb expression on CLL cells and functional responses to BCR and other receptor-mediated signals deserve further investigation.

Monoclonal B-Cell Lymphocytosis (MBL) Is Closely Related to Chronic Lymphocytic Leukemia (CLL) and May Be Better Classified as Early-Stage CLL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2349-2349
Author(s):  
Wolfgang Kern ◽  
Claudia Haferlach ◽  
Frank Dicker ◽  
Susanne Schnittger ◽  
Torsten Haferlach
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
Peripheral Blood ◽  
Early Stage ◽  
Normal Karyotype ◽  
Lymphocytic Leukemia ◽  
Cd38 Expression ◽  
Equity Ownership ◽  
Risk Parameters ◽  
Good Risk

Abstract Abstract 2349 Poster Board II-326 Monoclonal B-cell lymphocytosis (MBL) is separated from chronic lymphocytic leukemia (CLL) mainly by the somewhat arbitrary cut-off of 5000/μl CLL-phenotype cells in peripheral blood. While MBL in general shows an indolent clinical course this is also true for early-stage CLL. This may call into question the adequateness of separating MBL from CLL. Therefore, we prospectively analyzed a series of 298 cases with MBL by immunophenotyping, fluorescence in situ hybridization (FISH; probes for detection of del(6q21), del(11q22.3) (ATM), +12, del(13q14) (D13S25, D13S319), del(17p13) (TP53), and t(11;14)(q13;q32) (IGH-CCND1)), chromosome banding analysis (CBA) and molecular genetics (analysis of IgVH mutation status) for parameters which are established as prognostically relevant in CLL. Data was compared to a previously published series of 356 cases with CLL (Cytometry B Clin Cytom 2009;Epub.). Male:female ratio was similar for MBL and CLL (2.1:1 vs. 1.8:1, n.s.) as was mean±SD age (66.5±10.5 vs. 65.7±10.2 years, n.s.). Mean±SD cells with CLL phenotype in peripheral blood amounted to 2,417±1,497/μl in MBL and to 27,771±39,607/μl in CLL (p<0.001). ZAP-70 expression (mean±SD MFI ratio T-cells:B-cells 4.3±3.0 vs. 5.1±3.3, p=0.011) and CD38 expression (mean±SD % positive cells 33.5±28.9 vs. 26.5±31.5, p=0.004) were stronger in MBL. FISH analysis revealed similar frequencies of del(11q22.3) (8.1% vs. 11.7%, n.s.). In contrast, +12 (22.8% vs. 13.7%, p=0.003) and t(11;14) (2.1% vs. 0.0%, p=0.008) were observed more frequently in MBL while del(6q21) (1.8% vs. 6.1%, p=0.008), del(13q14) (45.1% vs. 64.3%, p<0.001), del(13q14) as sole abnormality (35.0% vs. 47.7%, p=0.002), and del(17q13) (1.4% vs. 8.0%, p<0.001) were more frequent in CLL. CBA demonstrated a normal karyotype (31.5% vs. 21.6%, p=0.004) and trisomies (10.7% vs. 6.2%, p=0.045) more often in MBL while deletions were observed less often (30.5% vs. 39.3%, p=0.021). Analysis of IgVH revealed a mutated status more frequently in MBL (76.3% vs. 60.6%, p<0.001). Thus, while some good risk parameters have been encountered more frequently in MBL compared to CLL there was no clear predominance of all good risk parameters but rather a mixed distribution between MBL and CLL. We next analyzed the prognostic impact of the above parameters in cases with MBL. Time to therapy (TTT) was negatively affected by a higher CD38 expression (p=0.007), del(11q22.3) (p=0.01), the presence of independent clones as identified by CBA, and an unmutated IgVH status (p=0.001). Multivariate analysis revealed a higher CD38 expression (p=0.026) as the only independent parameter affecting TTT. Overall survival (OS) was negatively affect by del(6q21) (p=0.001) and by the presence of independent clones as identified by CBA (p=0.056) while a normal karyotype by CBA was associated with a better OS (p=0.031). When analyzing both MBL and CLL cohorts together, +12 (p=0.011) was found to be related to shorter TTT and del(13q14) as sole abnormality (p=0.038) and a higher ZAP-70 ratio T-cells:B-cells (p=0.007) were related to longer TTT. Neither the amount of cells with CLL phenotype in peripheral blood nor the presence of MBL were significantly related to TTT. The only parameters independently related to TTT were del(11q22.3) (p=0.007) and +12 (p=0.037). Parameters negatively affecting OS were MBL (p=0.006), the presence of independent clones as identified by CBA (p=0.038) and a female gender (p=0.047). Multivariate analysis demonstrated MBL (p=0.021) and the presence of independent clones as identified by CBA (p=0.046) as independently related to OS. The present data indicates that biologic characteristics of CLL are found in MBL and that there is no general predominance of good risk parameters in MBL as compared to CLL. Thus, MBL may not be considered a distinct disease but rather an early stage of CLL. This is further supported by the lack of impact of MBL as compared to CLL on the TTT. Furthermore, it is suggested that cases classified as MBL should undergo assessment of prognostic parameters including CBA as one prognostic parameter as shown for CLL cases. Disclosures: Kern: MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

CD49d Expression Identifies a Chronic Lymphocytic Leukemia (CLL) Subset with High Levels of Circulating CD34 +Cells Co-Expressing Endothelial Cell Markers.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2329-2329
Author(s):  
Francesca Maria Rossi ◽  
Davide Rossi ◽  
Antonella Zucchetto ◽  
Riccardo Bomben ◽  
Michele Dal Bo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Bone Marrow Biopsies ◽  
Endothelial Markers ◽  
Cd38 Expression ◽  
Cell Counts ◽  
Cd34 Cells ◽  
Stromal Component ◽  
The Absolute

Abstract Abstract 2329 Poster Board II-306 Introduction: In chronic lymphocytic leukemia (CLL), CD49d, often in association with CD38, has been shown to mark a disease subset with poor prognosis. Functionally, both molecules act as counter-receptors for surface structures (i.e. VCAM-1/CD106 and CD31) usually expressed by the endothelial/stromal component of tumor micro-environment. We have recently identified a micro-environmental circuitry which involves CD38 triggering, and eventually determines an enrichment of the VCAM-1/CD106-expressing endothelial component detected in the context of CLL infiltrates found in bone marrow biopsies. Data was also provided that CD49d/VCAM-1 interactions are active in delivering pro-survival signals to CD49d-expressing CLL cells (Zucchetto et al, Cancer Res, 69, 4001, 2009). In this study, we investigated the amount of circulating progenitors with endothelial phenotype in CLL samples with different CD49d and CD38 expression levels. Methods: Peripheral blood (PB) samples from 91 CLL cases purposely selected with WBC>25,000/μl (B cells absolute lymphocyte count >10,000/μl) were evaluated by multiparametric flow cytometry for the absolute count of circulating CD34+ cells (ISHAGE protocol in single platform). Whenever possible (i.e. if a cluster of at least 100 CD34+ cells was detectable), a further characterization was performed (4-6 colours flow cytometry) for circulating endothelial cells (CEC), identified as a CD34+CD45low cell population co-expressing one of the following endothelial markers: CD309/VEGFR-2, CD144/VE-cadherin, CD106/VCAM-1 and CD146/Muc-18. CD49d and CD38 expression by CLL cells was considered positive if exceeding the standard cut-off value of 30% of positive cells. Results: PB absolute CD34+ cell counts were 7.5±7.5/μl in CD49d+ CLL (32 cases), vs. 3.3±2.7/μl in CD49d− CLL (59 cases; p=2.6×10−4), or 9.4±8.7/μl in CD49d+ CLL (30 cases) vs. 4.6±2.9/μl in CD49d− CLL (18 cases; p=0.004) when only cases phenotyped for CEC were considered. Furthermore, when samples were stratified also for CD38 expression, values of circulating CD34+ cells increased to 10.6±10.1/μl in CD38+CD49d+ CLL (11 cases) vs. 3.1±2.4/μl in CD38−CD49d− (51cases; p=1×10−5). Regarding the absolute quantification of CEC, a CD49d+ phenotype again marked the CLL subset with the highest CEC count, as identified by the expression of either the CD309/VEGFR-2 (CEC counts 1.7±2.3/μl in CD49d+ CLL vs. 0.5±0.5/μl CD49d− CLL; p=0.009) or the CD144/VE-cadherin (CEC counts 0.8±1/μl in CD49d+ CLL vs. 0.3±0.5/μl in CD49d− CLL; p=0.057) endothelial markers on CD34+CD45low cells. Notably, CEC from CD49d+ CLL expressed CD106/VCAM-1 in virtually all cells (1.6±2.4/μl), while the other marker of endothelial activation CD146/Muc-18 was detected in a fraction of CEC only (0.4±0.9/μl). Conclusions: CD49d and CD38 expression by CLL cells identify a disease subset with significantly higher number of both circulating CD34+ cells and CEC. This phenomenon could be explained considering several aspects: i) the sharing of common phenotypic markers between CLL cells and CD34+ progenitors, including CD38 and CD49d, which could be responsible for a displacement of CD34+ progenitors in the context of micro-environmental niches; ii) the known capacity of CLL cells, especially with a unmutated IGHV gene status and/or a CD38+CD49d+ phenotype to produce pro-angiogenic factors including Ang-2; iii) the rare PB cells expressing CD34 and CEC markers may represent CLL cell precursors with tumor-initiating cell features. Studies are currently ongoing to dissect among these hypotheses Disclosures: No relevant conflicts of interest to declare.

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