THE ROLE OF THE GENETIC ABNORMALITIES, EPIGENETIC AND microRNA IN THE PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA

2018 ◽  
Vol 40 (4) ◽  
pp. 261-267 ◽  
Author(s):  
K Tari ◽  
Z Shamsi ◽  
H Reza Ghafari ◽  
A Atashi ◽  
M Shahjahani ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
Bone Marrow Involvement ◽  
P53 Mutation ◽  
Lymphocytic Leukemia ◽  
Gene Promoters ◽  
Epigenetic Changes ◽  
Genetic Changes ◽  
Trisomy 12

Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

scholarly journals NEAT1 Long Isoform Is Highly Expressed in Chronic Lymphocytic Leukemia Irrespectively of Cytogenetic Groups or Clinical Outcome

2020 ◽  
Vol 6 (1) ◽  
pp. 11 ◽  
Author(s):  
Domenica Ronchetti ◽  
Vanessa Favasuli ◽  
Paola Monti ◽  
Giovanna Cutrona ◽  
Sonia Fabris ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcome ◽  
Risk Model ◽  
Therapeutic Potential ◽  
Multivariate Regression Analysis ◽  
Lymphocytic Leukemia ◽  
Mutational Status ◽  
Trisomy 12 ◽  
Time To First Treatment

The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in chronic lymphocytic leukemia (CLL) are still open questions. Herein, we investigated the significance of the lncRNA NEAT1 in CLL. We examined NEAT1 expression in 310 newly diagnosed Binet A patients, in normal CD19+ B-cells, and other types of B-cell malignancies. Although global NEAT1 expression level was not statistically different in CLL cells compared to normal B cells, the median ratio of NEAT1_2 long isoform and global NEAT1 expression in CLL samples was significantly higher than in other groups. NEAT1_2 was more expressed in patients carrying mutated IGHV genes. Concerning cytogenetic aberrations, NEAT1_2 expression in CLL with trisomy 12 was lower with respect to patients without alterations. Although global NEAT1 expression appeared not to be associated with clinical outcome, patients with the lowest NEAT1_2 expression displayed the shortest time to first treatment; however, a multivariate regression analysis showed that the NEAT1_2 risk model was not independent from other known prognostic factors, particularly the IGHV mutational status. Overall, our data prompt future studies to investigate whether the increased amount of the long NEAT1_2 isoform detected in CLL cells may have a specific role in the pathology of the disease.

Diagnostic and Clinical Considerations in Concomitant Bone Marrow Involvement by Plasma Cell Myeloma and Chronic Lymphocytic Leukemia/Monoclonal B-Cell Lymphocytosis: A Series of 15 Cases and Review of Literature

2013 ◽  
Vol 137 (4) ◽  
pp. 503-517 ◽  
Author(s):  
Christopher L. Alley ◽  
Endi Wang ◽  
Cherie H. Dunphy ◽  
Jerald Z. Gong ◽  
Chuanyi M. Lu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Correct Diagnosis ◽  
Bone Marrow Involvement ◽  
Rare Event ◽  
Lymphocytic Leukemia ◽  
Plasma Cell Myeloma

Context.—Plasma cell myeloma and chronic lymphocytic leukemia are both common hematologic malignancies, sharing many epidemiologic features. Concomitant detection of the 2 conditions poses special diagnostic challenges for the pathologist. Objective.—To describe the pathologic findings in cases of concomitant bone marrow involvement by myeloma and CD5+ monoclonal B cells and to outline the differential diagnostic possibilities, suggest a workup for correct diagnosis, and examine clinical outcome. Design.—Fifteen cases that met the diagnostic criteria were identified from pathology databases at 4 participating institutions. Morphologic findings were reviewed, additional immunohistochemical stains performed, and flow cytometric, cytogenetic, and relevant laboratory and clinical information was summarized. Previously published cases were searched from electronic databases and cross-references. Results.—Most patients (13 of 15) were older males. Often (11 of 15) they presented clinically with myeloma, yet had both monotypic plasma cells and B cells in the diagnostic marrow. In 4 patients, myeloma developed 24 months or later after chronic lymphocytic leukemia. In 7 patients, myeloma and CD5+ B cells showed identical immunoglobulin light-chain restriction. Primary differential diagnoses include lymphoplasmacytic lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia with plasmacytoid differentiation. CD56 and/or cyclin D1 expression by plasma cells was helpful for correct diagnosis. Most patients in our cohort and published reports were treated for plasma cell myeloma. Conclusions.—Concomitant detection of myeloma and chronic lymphocytic leukemia in the bone marrow is a rare event, which must be carefully differentiated from lymphomas with lymphoplasmacytic differentiation for correct treatment.

Low Expression of ROR1 on Chronic Lymphocytic Leukemia Is Associated with Other Atypical Findings

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4588-4588
Author(s):  
H. Elizabeth Broome ◽  
Laura Z. Rassenti ◽  
Michael Y. Choi ◽  
Thomas J. Kipps
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Confidence Interval ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Neoplastic Cells ◽  
Atypical Features ◽  
Trisomy 12 ◽  
Low Levels

Abstract Abstract 4588 ROR1 is a developmental embryonic surface antigen that also is expressed on chronic lymphocytic leukemia (CLL) cells, but not on most tissues or cells of healthy adults, including secondary lymphoid tissues or normal CD5 B cells. Studies involving relatively small numbers of patients have identified expression of ROR1 on the neoplastic cells of nearly all patients examined. However, it is not established whether there are cases of bona fide CLL that lack expression of this antigen or whether cases of putative CLL that lack expression of ROR1 actually represent a disease subset that has biologic and/or clinical features distinct from that of CLL that express ROR1. To further explore the significance of low levels of ROR1 on CLL, we analyzed 268 cases of CLL for surface expression of ROR1 via multiparameter flow cytometry using a fluorochrome-conjugated mAb specific for ROR1. The percentage of CLL cells with ROR1 for each case had a median of 94, mean of 81 and a standard deviation of 26. By visual inspection of the histograms, the distribution of ROR1 expression for each case approximated that of a Gaussian distribution. For 14 of these cases (5.2%), less than 20% of their neoplastic B cells expressed ROR1. Three of these 14 cases (21%) had features of “typical” CLL by immunophenotype. These cases did not have cytogenetic abnormalities as detected by fluorescence in situ hybridization (FISH), were negative for ZAP-70, and expressed mutated IGHV genes (Table 1). The 11 other cases had some features in common with that of typical CLL including small, mature, lymphocyte morphology, a persistent absolute lymphocyte count of greater than 5K/ul, expression of CD5, and lack of translocations characteristic of mantle cell lymphoma [e.g t(11;14)]. However, these 11 cases also showed variably atypical features. Three cases had dim or partial expression of CD23 (cases #1, 8, 11), one case lacked expression of CD23 (#4). Trisomy 12 was detected in three of the 14 cases (21%; 95% confidence interval 8–48%), not significantly different than the reported frequency of 14%. 13qdel as the sole cytogenetic/ FISH abnormality was present in another three of the 14 cases (21%; 95% confidence interval 8–48%), which is significantly lower than the reported frequency of 60% (p<0.05). The clonal IGHV gene had somatic mutations in 9 of 12 cases analyzed (75%; 95% confidence interval 47–91%). These findings indicate that low levels of ROR1 are rare in typical CLL, and that CLL with low level expression of ROR1 have a high frequency of other atypical immunophenotypic and cytogenetic findings.Table 1Case% ROR1Atypical features of ImmunophenotypeCytogenetics/ FISH% ZAP- 70% IGHV homologyALC1*1.6partial 23+, bright 79b+, dim 81+, FMC7+Normal FISH2691.740.322.0dim 5+, 13+, FMC7+46, XX, t(13;18) (q14q21) [4]/46,XX916); 13qdel by FISHNANA12.133.138+47, XY, del(2)(p23),+12(14) (?q24); trisomy 12 by FISH1100.017.34*3.4dim 5+, bright 20+, 23-neg, FMC7+, bright sIg+46, XY; 13qdel by FISH194.7193.454.0Typical46,XY; normal FISH195.58.46*5.7TypicalNormal FISH2194.028.177.4TypicalNormal FISH1592.716.38*7.7Dim 23+, bright 79b+, variable 81+, bright sIg+46 XY; 13qdel by FISH7491.03.098.3NANA1093.454.61013.713+, bright 20+, 38+, FMC7+NA1098.614.61114.1weak 5+, 13+, dim 23+, FMC7+del13q by FISH2793.13.012*14.138+Trisomy 1287100.046.813*15.2mod 20+, partial FMC7+NA1897.912.514*16.413+, 38+, FMC7+,47, XX,+12[7]/47,idem,?2q,-8,add(10(p13),+mar[3]; trisomy 12 by FISHNANA5.2*= splenomegaly%4A5 is percentage of CD19+ lymphocytes with 4A5 fluorescence greater than threshold set with 99% of fluorescence from isotype control staining.Immunophenotype is considered “typical” for CLL if neoplastic cells express CD5, CD19, CD20 (dim), CD23, CD43 (dim), CD79b(dim) and do NOT express CD38, CD81 and FMC-7. Only the atypical features for each case are noted in table.Cytogenetics/FISH: 20 metaphase karyotype and/or 200 interphase FISH for CCND1/IGH [translocation (11;14)(q13;q32)], ATM (11q22.3), D12Z3 (12 centromere), D13S319 (13q14.3), LAMP1 (13q34), p53 (17p13.1).% Zap-70 is percentage of CD19+ neoplastic cells that express ZAP70 by flow cytometry.% IgH mut. is the percentage homology of the neoplastic clone with germline IgHV geneALC is absolute lymphocyte countNA: not available Disclosures: No relevant conflicts of interest to declare.

scholarly journals Characterization of Long Non-Coding RNAs in Chronic Lymphocytic Leukemia: Evidence for Association with Disease Progression in Trisomy 12 Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3281-3281
Author(s):  
Renee C. Tschumper ◽  
Tait D. Shanafelt ◽  
Neil E. Kay ◽  
Diane F. Jelinek
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Disease Progression ◽  
Research Funding ◽  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
Lncrna Expression ◽  
Trisomy 12 ◽  
Non Coding Rnas

Abstract BACKGROUND: Chronic lymphocytic leukemia (CLL) is a heterogeneous B cell malignancy with patients being categorized into disease subsets based on several key biologic parameters, e.g., mutation status (mutated, M; or unmutated, UM) of the immunoglobulin heavy chain variable region (IGHV), acquired chromosomal abnormalities, and expression of CD38 and CD49d. Furthermore, about one third of CLL patients express stereotyped B cell receptors and/or may acquire high risk common mutations in genes such as NOTCH1 and SF3B1 suggesting ongoing genetic evolution as drivers of disease development. Critical to this concept, those CLL patients with trisomy 12 (T12) defects have a higher incidence of mutations in NOTCH1 and often have a stereotyped receptor. However, T12 patients may have a variable clinical course that appears to be unrelated to these 2 drivers suggesting an additional, possibly non-coding genetic component that may further impact disease progression in these patients. One potentially relevant genetic factor that could influence T12 clinical course is long non-coding RNAs (lncRNAs). LncRNAs are transcripts longer than 200 nucleotides that can affect a number of cellular processes. Importantly, lncRNAs have been implicated in various cancers including malignant hematopoiesis indicating they could be therapeutic targets and/or clinically useful biomarkers. METHODS: To pursue a role for lncRNAs in T12 we used v3.0 Arraystar Human LncRNA Microarrays to assess the global profile of lncRNA expression in CLL with an emphasis on patients with T12. Two cohorts of 6 patients with T12 were selected for comparison: one defined as progressive with a short time to treatment (TTT) (treatment ≤1 year after diagnosis) and one as indolent (no treatment > 5 years after diagnosis). Each cohort included 3 patients with M and 3 with UM IGHV status. RNA from normal CD5+ and CD5- B cells was included as a control. To compensate for the small sample size in each cohort, a significant difference in lncRNA expression between the groups was defined as a fold change (FC) ≥5.0, p-value ≤0.05 and false discovery rate (FDR) ≤ 0.05. RESULTS: An initial global comparison of CD5+/CD5- normal B cells vs all CLL samples found that 609 lncRNAs were differentially expressed using the criteria listed above with 158 lncRNAs having a FC>10. Notable lncRNAs in this group included: LOC541472 (down in CLL and associated with the IL-6 gene), D63785 (up in CLL and associated with TBC1D3C, an oncoprotein), CTC-459I6.1 (up in CLL and associated with RASGRF2) and AC002480.5 (down in CLL and associated with STEAP1B, shown to be overexpressed in prostate cancer). We next evaluated T12 samples and identified 90 candidate lncRNAs that may discriminate between progressive and indolent T12 cases. Within this group were 11 lncRNAs with a FC > 10, 5 of which have no known associated gene. Of those associated with known genes, 3 were ultra-conserved region encoding lncRNAs down-regulated in progressive T12 patients (TTT ≤1 yr) and linked to hephaestin-like protein 1 precursor, pannexin-1, and tubulin beta-3 chain isoform 1. Of potential high relevance we found that the lncRNA LPP-AS1 was down-regulated in progressive T12 patients (TTT ≤1 yr) and known to be associated with the LIM-containing lipoma preferred partner (LPP) gene (p=0.028; FDR=0.03 and FC=18.3). Looking specifically at IGHV M progressive T12 patients (T12M≤1 yr) vs IGHV M indolent T12 patients (T12M>5 yrs), we again found the LPP-AS1 lncRNA was highly down-regulated in T12M≤1 (p=0.00046; FDR=0.006 and FC=34.5) but it was not found to be differentially expressed in the UM T12≤1 yr vs UM T12>5 yr comparison. The LPP gene has been shown to play a role in cell-cell adhesion, motility and signaling, and is often the fusion partner for the mixed lineage leukemia (MLL) gene in secondary acute leukemia. Furthermore, LLP may play a role in breast cancer cell invasion. LPP-AS1 may be participating in IGHV M T12 progression by affecting LPP and thus influencing migration through the lymph node microenvironment. CONCLUSION: While candidate lncRNAs in T12 CLL need to be validated, the LPP-AS1 lncRNA shows promise as a possible marker and potential treatment target for those patients with T12 and M IGHV that may progress rapidly. Further studies are needed to evaluate the impact of lncRNAs on clinical outcome of T12 CLL patients. Disclosures Shanafelt: Hospiria: Research Funding; Pharmacyclics/Jannsen: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; glaxoSmithKline: Research Funding; Genetech: Research Funding; Polyphenon E Int'l: Research Funding. Kay:Celgene: Research Funding.

Tumor Antigen ROR1 Targeted Delivery Of FTY720 Derivative OSU-2S Prolongs Survival In ROR1 Engineered Mouse Model Of Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4168-4168
Author(s):  
Rajeswaran Mani ◽  
Yicheng Mao ◽  
Frank W Frissora ◽  
Chi-ling Chiang ◽  
Jiang Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Mouse Model ◽  
B Cell ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
Orphan Receptor ◽  
B Cell Malignancies

Abstract The discovery of predominantly inactive phosphatases in a variety of cancers and the potential for phosphatase targeted therapy as an alternative to kinase inhibitors especially in situations where the efficacy of the kinase inhibitors are compromised due to resistance mechanisms attributed to mutations and single nucleotide polymorphisms of the drug targets prompted us to evaluate potential activators of phosphatases in chronic lymphocytic leukemia (CLL) and other B cell malignancies. We have recently identified cytotoxic activity of OSU-2S, a novel non-immunosuppressive FTY720 derivative and PP2A activator against CLL. OSU-2S induced cytotoxicity was associated with PKC dependent phosphorylation of Serine 591 (S591) of tumor suppressor phosphatase SHP1 and its nuclear translocation consistent with a potential role for S591 phosphorylation. Here in, we demonstrate the molecular mechanisms and a rational approach for developing this novel agent for preclinical and clinical studies. In-vitro kinase assay demonstrated OSU-2S increased activity of purified PKC directly (p<0.0001) and also in CLL-B cells (N=5; p<0.05). Further, OSU-2S induced phospho SHP1S591 is inversely correlated with viability in CLL-B cells (N=20; rs= -0.64; p=0.0026). To elucidate the role of nuclear phospho SHP1S591, we performed gene expression studies by microarray analysis of RNA isolated from OSU-2S treated CLL cells revealing at least 260 genes that have changed by two fold (p<0.0005). Ingenuity pathway analysis (IPA) of the top 40 genes included some of B cell receptor (BCR) signaling candidates such as PI3Kγ, PLCγ, MAP2K6. Consistent with this, OSU-2S treatment reduced BCR activation of CLL cells stimulated with goat F(ab’)2 against human IgA+IgG+IgM (H+L), as identified with reduced activation and viability. Moreover, with relevant to CLL disease Tcl1A expression that was identified to be down regulated in response to OSU-2S in the gene expression profile was independently confirmed to be significantly down regulated both at the mRNA (N=7; p=0.0159) and protein levels with the corresponding up regulation in cFOS and FRA2 two known inhibitory targets of Tcl1A. To overcome the limitations associated with non specific activity on unintended target cells and normal counterparts, we made OSU-2S immunoliposome (2A2-OSU-2S-ILP) formulation targeting malignant B cell specific tumor antigen receptor tyrosine kinase-like orphan receptor (ROR1). ROR1 is an orphan receptor tyrosine kinase that is expressed exclusively in malignant B but not normal B cells. We have used a non-cytotoxic anti-ROR1 monoclonal antibody 2A2 to formulate immunoliposome 2A2-ILP which showed selective binding and internalization in ROR1+ CLL B cells but not ROR1- normal B cells from healthy donors. To demonstrate the chemotherapeutic efficiency in a more relevant CLL model in-vivo, we have generated Eµ-hROR1 transgenic mouse which expresses B cell specific human ROR1. Crossing the Eµ-hROR1 mouse with Eµ-Tcl1 CLL mouse resulted in generation of Eµ-hROR1-Tcl1 mouse that exhibit CLL like disease with human ROR1 antigen in leukemic CD19+CD5+ B cells. Ex-vivostudies using CLL primary B cells or Eµ-hROR1-Tcl1 double transgenic mouse B cells showed selective toxicity of leukemic B cells by 2A2-OSU-2S-ILP compared to 2A2-Empty-ILP which does not have OSU-2S. Further, administration of 2A2-OSU-2S-ILP in Eμ-hROR1 transgenic mice resulted in selective depletion of ROR1 positive B cells and prolonged survival in Eµ-hROR1-Tcl1 spleen engrafted mouse model of CLL (N=11 for 2A2-OSU-2S-ILP and N=9 for 2A2-Empty-ILP; p<0.001). The novel OSU-2S, its delivery formulation, and the mouse models described here provide the tools for further development of OSU-2S formulations for B cell malignancies. Disclosures: No relevant conflicts of interest to declare.

Trisomy 12 in B Cells of Patients with B-Cell Chronic Lymphocytic Leukemia

1986 ◽  
Vol 314 (14) ◽  
pp. 865-869 ◽  
Author(s):  
Sakari Knuutila ◽  
Erkki Elonen ◽  
Lasse Teerenhovi ◽  
Leena Rossi ◽  
Ritva Leskinen ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Trisomy 12 ◽  
Cell Chronic Lymphocytic Leukemia

B-Cell Chronic Lymphocytic Leukemia: A Bird of a Different Feather

1999 ◽  
Vol 17 (1) ◽  
pp. 399-399 ◽  
Author(s):  
Federico Caligaris-Cappio ◽  
Terry J. Hamblin
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Biology ◽  
Lymphocytic Leukemia ◽  
Accessory Cells ◽  
Trisomy 12 ◽  
Autoimmune Cytopenias ◽  
Cell Chronic Lymphocytic Leukemia ◽  
Self Antigens

PURPOSE: To review the recent major advances in the molecular and cell biology of B-cell chronic lymphocytic leukemia (B-CLL). METHODS: We analyzed the nature of malignant B-CLL B cells and their interactions with the microenvironment. RESULTS: B-CLL is a malignancy of a mantle zone-based subpopulation of anergic, self-reactive, activated CD5+ B cells devoted to the production of polyreactive natural autoantibodies. It is the quintessential example of a human malignancy that primarily involves defects in the induction of programmed cell death. An abnormal karyotype is observed in about 50% of patients with B-CLL. Patients with 13q14 abnormalities show heavy somatic mutation and have a benign disease. Trisomy 12 is associated with unmutated VH genes, atypical cellular morphology, and progressive disease. Extended cell survival is further shielded by a kinetic refractoriness likely promoted by abnormalities of the B-cell antigen receptor complex and favored by some cytokines that highlight a reciprocal dialog between malignant B and T cells. Because the tumor cells act as the major accessory cells, the accumulating malignant B-cell population per se is a hurdle to the production of normal antibodies and leads to a progressive and severe hypogammaglobulinemia. Conceivably, in the presence of certain immunoglobulin genes and when the T-cell control becomes deficient, activated malignant B cells may become able to present self-antigens and drive residual normal B cells to produce polyclonal autoantibodies restricted to self-antigens expressed only by blood cells and cause autoimmune cytopenias. CONCLUSION: The distinctiveness of B-CLL B cells explains why B-CLL is different from other B-cell tumors and accounts for the development of immune deficiency and autoimmunity.

scholarly journals Therapeutic molecules targeting the malignant B cell microenvironment of chronic lymphocytic leukemia

2019 ◽  
Vol 2 (1) ◽  
pp. 17-29
Author(s):  
Georgiana Ene ◽  
Ana Maria Vladareanu ◽  
Horia Bumbea
Keyword(s):  
B Cells ◽  
Tumor Microenvironment ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Suppressor Cells ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Treatment Modalities ◽  
Current Standard

Although valuable advances have been made in the hematological field over the past years, most of the B-cell malignancies remain incurable, as malignant B cells retain the ability to respond to a variety of microenvironment signals, providing additional opportunities in the development of therapeutic interactions. The role that the microenvironment has in the natural history of malignant B cell of chronic lymphocytic leukemia (CLL) appears to favor the development of new treatment modalities aimed at interrupting the interaction between malignant B cells and microenvironment. At this moment, the therapeutic approaches whose target is the CLL microenvironment or the signaling pathways associated with CLL microenvironment are one of the most important therapeutic strategy. Interactions taking place within the tumor microenvironment are targeted by multiple clinical trials, and preliminary results are favorable. Chronic Lymphocytic Leukemia (CLL) is a size of complexity because leukemic cells are grown and protected by anti-cancer therapies by the components constituting the tumor microenvironment in lymphoid organs (e.g., endothelial cells, dendritic cells (CD), T cells, myeloid-derived suppressor cells (MDSCs), monocyte-derived nurse-like cells (NLC))[1] Current standard therapy in CLL combines chemotherapy with an anti-CD20 monoclonal antibody. This combination induces substantial toxicity and is not curative, as most patients relapse. Recent advances using kinase inhibitors, such as ibrutinib and idelalisib or BCL2 signaling inhibitors e.g Venetoclax, indicate a major change promising to treat chronic lymphocytic leukemia without chemotherapy. At present, these therapeutic agents do not provide complete responses and should be administered continuously by the patient in order to avoid recurrence/relapse of the disease. Resistance to ibrutinib has already been detected in patients with high genetic risk. [2] This problem requires the identification of therapies that combine agents with distinct mechanisms of action.

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