scholarly journals Isoform-selective phosphoinositide 3′-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell–mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach

Blood ◽  
2009 ◽  
Vol 113 (22) ◽  
pp. 5549-5557 ◽  
Author(s):  
Matthias Niedermeier ◽  
Bryan T. Hennessy ◽  
Zachary A. Knight ◽  
Marina Henneberg ◽  
Jianhua Hu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Lymphocytic Leukemia ◽  
Stromal Cell ◽  
Actin Polymerization ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
Pi3k Inhibitors ◽  
Cxcr4 Signaling ◽  
Phosphoinositide 3 Kinase ◽  
Induced Apoptosis

Phosphoinositide 3-kinases (PI3Ks) are among the most frequently activated signaling pathways in cancer. In chronic lymphocytic leukemia (CLL), signals from the microenvironment are critical for expansion of the malignant B cells, and cause constitutive activation of PI3Ks. CXCR4 is a key receptor for CLL cell migration and adhesion to marrow stromal cells (MSCs). Because of the importance of CXCR4 and PI3Ks for CLL-microenvironment cross-talk, we investigated the activity of novel, isoform-selective PI3K inhibitors that target different isoforms of the p110-kDa subunit. Inhibition with p110α inhibitors (PIK-90 and PI-103) resulted in a significant reduction of chemotaxis and actin polymerization to CXCL12 and reduced migration beneath MSC (pseudoemperipolesis). Western blot and reverse phase protein array analyses consistently demonstrated that PIK-90 and PI-103 inhibited phosphorylation of Akt and S6, whereas p110δ or p110β/p110δ inhibitors were less effective. In suspension and MSC cocultures, PI-103 and PIK-90 were potent inducers of CLL cell apoptosis. Moreover, these p110α inhibitors enhanced the cytotoxicity of fludarabine and reversed the protective effect of MSC on fludarabine-induced apoptosis. Collectively, our data demonstrate that p110α inhibitors antagonize stromal cell-derived migration, survival, and drug-resistance signals and therefore provide a rational to explore the therapeutic activity of these promising agents in CLL.

Standardizing Co-Culture Conditions Between Chronic Lymphocytic Leukemia Cells and Marrow Stromal Cells: Towards a Reliable and Reproducible System to Assess Cell Adhesion-Mediated Drug Resistance

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3149-3149
Author(s):  
Antonina Kurtova ◽  
Maite P. Quiroga ◽  
William G. Wierda ◽  
Michael Keating ◽  
Jan A. Burger
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Chronic Lymphocytic Leukemia ◽  
Stromal Cells ◽  
Lymphocytic Leukemia ◽  
Marrow Stromal Cells ◽  
Hpv E6 ◽  
Induced Apoptosis

Abstract Contact between chronic lymphocytic leukemia (CLL) cells and accessory stromal cells in tissue microenvironments is considered to play a major role in regulating CLL cell survival and disease progression. Stromal cells of various origins and species, and variable stromal-CLL cell ratios have been used in the past to study CLL-stromal cell interactions and to assess cell-adhesion mediated drug resistance (CAM-DR). Because of the heterogeneity of the currently used in vitro systems to study CLL-MSC interactions, and the importance of these co-culture systems for development and testing of novel agents, we tested a panel of murine and human MSC lines for their capacities to support CLL cell survival and CAM-DR, using various CLL-MSC ratios and fludarabine (F-ara-A) to induce CLL cell apoptosis. We tested four murine, non-transformed MSC lines derived from bone marrow: M210B4, KUM4, ST-2 and KUSA-H1. Also, we tested three human transformed cell lines: Stroma-NKtert, derived from bone marrow and immortalized by human telomerase reverse transcriptase (hTERT), UE6E7-T2 derived from bone marrow and transformed with human papilloma viruses (HPV) E6, E7 and hTERT, and UCB408E6E7Tert33 derived from umbilical cord blood and transformed with hTERT and HPV E6, E7. CLL cells were isolated from peripheral blood of untreated patients and each cell line was tested with at least three different patients according to the following protocol: viability of CLL was tested after 24, 48 and 72 hours by flow cytometry after staining with DiOC6 and propidium iodide. The following conditions were assayed on each of the MSC lines: CLL cells in suspension culture, CLL cells in suspension culture with 10 mM F-ara-A, CLL cells in co-culture with MSC, and CLL cells in co-culture with MSC and with 10 mM F-ara-A. Firstly, we performed titration experiments in order to identify the most appropriate ratio between stromal and CLL cells, using CLL-MSC ratios of 5:1, 10:1, 20:1, 50:1 and 100:1. We found a decline in MSC-derived CLL cell protection at the highest ratio of 100:1, suggesting that ratios of 50:1 or lower provide optimal conditions for in vitro assays. Results shown in Table 1 were assayed using a 20:1 ratio and represented relative viabilities when compared to untreated controls (mean±SEM). Regarding the protective effect of different MSC, we found that all MSC lines demonstrated remarkable protection of CLL cells from spontaneous and F-ara-A-induced apoptosis. We also found that stromal cells that had round shape morphology and easily formed confluent monolayer (M210B4, KUSA-H1, Stroma-NKTert) showed more prolonged protective effect in comparison to cell lines with more spindle shaped morphology (ST-2, KUM4, UE6E7-T2). The failure of UE6E7-T2 and UCB408E6E7Tert33 to demonstrate long-term protection of CLL cells could be related to their own sensitivity to F-ara-A. In this comparative study we demonstrated that both murine and human MSC provide substantial and comparable levels of protection from spontaneous and drug-induced apoptosis. CLL:MSC ratios of 50:1 or lower can be considered ideal for co-culture experiments. Further experiments have to be done to determine the levels of MSC-derived protection in a larger series of CLL samples and in different laboratories for validation. Collectively, in these co-culture assays we can study CLL-MSC interactions and CLL drugs under more standardized conditions that may allow us to evaluate the efficacy of new treatments that target the CLL microenvironment. Time points 24 hours 48 hours 72 hours +Flu + MSC + MSC +Flu +Flu + MSC + MSC +Flu +Flu +MSC + MSC +Flu M210B4 85.2±2.4 117.2±5.0 110.5±4.9 30.8±12.6 138.1±9.5 113.0±2.2 5.2±3.1 138.1±5.1 120.4±3.4 ST-2 93.6±3.0 99.9±2.6 103.1±0.5 51.6±9.4 111.9±2.6 89.8±8.7 13.9±6.3 112.6±5.7 87.0±16.4 KUM-4 93.6±3.0 106.4±1.8 104.2±1.9 51.6±9.4 112.4±2.6 100.8±2.8 13.9±6.3 111.8±6.7 88.5±11.4 KUSA-H1 79.4±7.4 125.1±3.7 118.2±2.0 33.9±10.9 136.0±3.6 107.2±7.0 11.3±6.1 133.6±5.4 84.9±7.6 Stroma-NKTert 79.3±7.0 118.6±7.0 111.0±7.0 30.5±9.5 130.7±9.5 115.6±8.0 7.1±4.3 133.0±11.5 122.7±9.0 UE6E7-T2 79.3±7.0 113.4±3.9 109.3±3.0 30.5±9.5 118.4±4.8 85.0±7.1 7.1±4.3 119.2±6.9 51.0±10.1 UCB408 E6E7Tert33 81.5±7.2 120.2±5.4 111.8±2.7 36.7±9.4 123.7±6.3 86.7±7.7 8.5±6.7 119.7±6.1 50.8±13.0 Table 1. Flu: fludarabine (10mM/ml), MSC: marrow stromal cells

Chronic Lymphocytic Leukemia B Cells Express Functional CXCR4 Chemokine Receptors That Mediate Spontaneous Migration Beneath Bone Marrow Stromal Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3658-3667 ◽  
Author(s):  
Jan A. Burger ◽  
Meike Burger ◽  
Thomas J. Kipps
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Pertussis Toxin ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Actin Polymerization ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Marrow Stromal Cells

Chemokines play a central role for lymphocyte trafficking and homing. The mechanisms that direct the tissue localization of B cells from patients with chronic lymphocytic leukemia (B-CLL) are unknown. We found that CLL B cells express functional CXCR4 receptors for the chemokine stromal cell-derived factor-1 (SDF-1), as demonstrated by receptor endocytosis, calcium mobilization, and actin polymerization assays. Moreover, CLL B cells displayed chemotaxis to this chemokine that could be inhibited by monoclonal antibodies (MoAbs) against CXCR4, pertussis toxin, or Wortmannin, a phosphatidylinositol 3-kinase inhibitor. That this chemotaxis may be involved in the homing of CLL cells is argued by studies in which CLL B cells were cocultured with a murine marrow stromal cell line that secretes SDF-1. Within 2 hours, CLL B cells spontaneously migrated beneath such stromal cells in vitro (pseudoemperipolesis). This migration could be inhibited by pretreatment of CLL B cells with anti-CXCR4 MoAbs, SDF-1, or pertussis-toxin. Furthermore, we noted strong downmodulation of CXCR4 on CLL B cells that migrated into the stromal cell layer. These findings demonstrate that the chemokine receptor CXCR4 on CLL B cells plays a critical role for heterotypic adherence to marrow stromal cells and provide a new mechanism to account for the marrow infiltration by neoplastic B cells.

scholarly journals CD160 signaling mediates PI3K-dependent survival and growth signals in chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (15) ◽  
pp. 3079-3088 ◽  
Author(s):  
Feng-Ting Liu ◽  
Jerome Giustiniani ◽  
Timothy Farren ◽  
Li Jia ◽  
Armand Bensussan ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Cycle Progression ◽  
Lymphocytic Leukemia ◽  
Cytochrome C Release ◽  
Pi3k Inhibitors ◽  
Phosphoinositide 3 Kinase ◽  
Dose Dependent

Abstract B-cell chronic lymphocytic leukemia (CLL) expresses CD160, a glycosylphosphatidylinositol-linked receptor found on normal natural killer (NK) and T cells, but not B cells. CD160 is a multifunctional molecule in normal lymphocytes, but its role in CLL biology is unknown. In vitro, CLL cells undergo rapid spontaneous apoptosis, which CD160 activation protected against—mean cell viability increased from 67% to 79% (P < .001). This was associated with up-regulation of Bcl-2, Bcl-xL, and Mcl-1, but not Bax. As expected from these changes in Bcl-2/Bax and Bcl-xL/Bax ratios, CD160 triggering reduced mitochondrial membrane potential collapse and cytochrome c release. CD160 stimulation also induced DNA synthesis, cell cycle progression, and proliferation. B-cell antigen receptor (BCR)–induced CLL proliferation was generally greater than with CD160, but marked variation was seen. Both BCR and CD160 signaling led to CLL secretion of interleukin-6 (IL-6) and IL-8, although CD160 induced greater increases of IL-6 (51-fold) and IL-8 (15-fold). Survival and activation signals mediated by CD160 showed dose-dependent suppression by phosphoinositide-3 kinase (PI3K) inhibitors. Thus, in vitro, CLL cells can use the CD160 pathway for survival and activation, mimicking CD160 signaling in normal NK and CD8+ T cells. Establishing the pathophysiologic relevance of these findings may reveal new therapeutic targets.

Chronic Lymphocytic Leukemia B Cells Express Functional CXCR4 Chemokine Receptors That Mediate Spontaneous Migration Beneath Bone Marrow Stromal Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3658-3667 ◽  
Author(s):  
Jan A. Burger ◽  
Meike Burger ◽  
Thomas J. Kipps
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Pertussis Toxin ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Actin Polymerization ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Marrow Stromal Cells

Abstract Chemokines play a central role for lymphocyte trafficking and homing. The mechanisms that direct the tissue localization of B cells from patients with chronic lymphocytic leukemia (B-CLL) are unknown. We found that CLL B cells express functional CXCR4 receptors for the chemokine stromal cell-derived factor-1 (SDF-1), as demonstrated by receptor endocytosis, calcium mobilization, and actin polymerization assays. Moreover, CLL B cells displayed chemotaxis to this chemokine that could be inhibited by monoclonal antibodies (MoAbs) against CXCR4, pertussis toxin, or Wortmannin, a phosphatidylinositol 3-kinase inhibitor. That this chemotaxis may be involved in the homing of CLL cells is argued by studies in which CLL B cells were cocultured with a murine marrow stromal cell line that secretes SDF-1. Within 2 hours, CLL B cells spontaneously migrated beneath such stromal cells in vitro (pseudoemperipolesis). This migration could be inhibited by pretreatment of CLL B cells with anti-CXCR4 MoAbs, SDF-1, or pertussis-toxin. Furthermore, we noted strong downmodulation of CXCR4 on CLL B cells that migrated into the stromal cell layer. These findings demonstrate that the chemokine receptor CXCR4 on CLL B cells plays a critical role for heterotypic adherence to marrow stromal cells and provide a new mechanism to account for the marrow infiltration by neoplastic B cells.

Possible Mechanisms Of Resistance To The Novel BH3-Mimetic ABT-199 In In Vitro Lymph Node Models Of CLL – The Role Of Abl and Btk

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4188-4188 ◽  
Author(s):  
Rachel Thijssen ◽  
Christian R Geest ◽  
Martin FM de Rooij ◽  
Nora Liu ◽  
Bogdan I Florea ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Lymph Node ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Application ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Solid Phase ◽  
Lymphocytic Leukemia ◽  
Bh3 Mimetic

Abstract The new BH3-mimetic ABT-199 antagonizes Bcl-2 and avoids the thrombocytopenia associated with clinical application of its predecessor ABT-263 (navitoclax). Chronic lymphocytic leukemia (CLL) cells are highly sensitive to ABT-199 and the first clinical results show clear reductions in peripheral and bone marrow CLL cells and in lymph node size. In the lymph node, CLL cells receive pro-survival signals that upregulate Bcl-XL, Mcl-1 and Bfl-11. These Bcl-2 family members are not targeted by ABT-199, which poses the potential risk of remaining clones with residual viability. Here, we aimed to define the signals that determine sensitivity for ABT-199 and ABT-737 in an in vitro lymph node model of CLL. We applied CD40 and cytokine stimulation in combination with kinase inhibitors that are known to change microenviroenmental signals and increase drug resistance in CLL. Stimulation via CD40 plus IL-4 or IL-21 differentially affected the expression of Mcl-1, Bcl-XL, Bfl-1 and Noxa and this correlated with strong alterations in sensitivity to ABT-737 and ABT-199 (see table 1 for LC 50 values). As reported before2, in vitro CD40 stimulation reduced sensitivity to ABT-737 by 100-fold, and this was further decreased by IL-4. Strikingly, CD40+IL-4 stimulation in primary CLL cells resulted in full resistance to 10 μM ABT-199, probably due to very high levels of Bcl-XL.Table 1The LC50 of ABT-737 or ABT-199 for CLL cells stimulated with CD40L and IL-21 or IL-4 (averaged values n=8)StimulationLC50 (μM)ABT-737ABT-1993T3 (control)0.0050.0013T40L0.781> 103T40L + IL-210.1950.210 3T40L + IL-46.772> 103T40L + IL-21 + IL-40.4269.121 We next sought ways to circumvent resistance against ABT-199 induced in our in vitro model. We showed previously that the broad spectrum kinase inhibitor dasatinib prevented CD40-mediated resistance to various drugs, including ABT-7373. We therefore first characterized the targets of dasatinib in primary CLL by solid-phase pull-down, mass-spectrometry and competition binding. Abl and Btk were identified as dominant and specific interactors of dasatinib. Importantly, resistance for BH3-mimetics could be overcome by dasatinib (see table 2) and the Abl inhibitor imatinib, but not by the more selective Btk inhibitor ibrutinib. Conversely, BCR- and chemokine-controlled adhesion could be abolished by dasatinib and ibrutinib, but not by imatinib. Thus, Abl and Btk function in two key pro-survival arms; chemoresistance and localization in the protective environment.Table 2The LC50 of ABT-737 or ABT-199 for CLL cells stimulated with CD40L in combination with Dasatinib (averaged values n=4)StimulationLC50 (μM)ABT-737ABT-1993T30.0050.0013T40L0.781> 103T40L + 100 nM Dasatinib0.0810.066 3T40L + 1000 nM Dasatinib0.0370.020 The observed resistance to ABT-199 induced in our in vitro a co-culture system designed to simulate the CLL microenvironment does not reflect the observations from clinical trials in patients. Nevertheless, long-term clinical application of ABT-199 in CLL might select for resistant clones at protective niches. Our data suggest that this may be overcome by combination treatment with kinase inhibitors that either directly abrogate anti-apoptotic signals or cause egress from lymph node sites and prevent the resistance mechanism from coming into play. 1. Smit LA, Hallaert DY, Spijker R et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocitic leukemia cells correlates with survival capacity. Blood 2007;109:1660-1668. 2. Vogler M, Butterworth M, Majid A et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 2009;113:4403-4413. 3. Hallaert DY, Jaspers A, van Noesel CJ et al. c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL; Implications for therapeutic targeting of chemoresistant niches. Blood 2008;112:5141-5149. Disclosures: No relevant conflicts of interest to declare.

Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1824-1830 ◽  
Author(s):  
Meike Burger ◽  
Tanja Hartmann ◽  
Myriam Krome ◽  
Justyna Rawluk ◽  
Hirokazu Tamamura ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Stromal Cells ◽  
Chemokine Receptors ◽  
Actin Polymerization ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Cxcr4 Antagonists ◽  
Induced Apoptosis

Abstract Growth and survival of chronic lymphocytic leukemia (CLL) B cells are favored by interactions between CLL and nontumoral accessory cells. CLL cells express CXCR4 chemokine receptors that direct leukemia cell chemotaxis. Marrow stromal cells or nurselike cells constitutively secrete CXCL12, the ligand for CXCR4, thereby attracting and rescuing CLL B cells from apoptosis in a contact-dependent fashion. Therefore, the CXCR4-CXCL12 axis represents a potential therapeutic target in CLL. We evaluated the most active CXCR4-specific antagonists (T140, TC14012, TN14003) for their capacity to inhibit CXCL12 responses in CLL cells. T140, or its analogs, inhibited actin polymerization, chemotaxis, and migration of CLL cells beneath stromal cells. CXCL12-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) was abolished by CXCR4 antagonists. TC14012 and TN14003 antagonized the antiapoptotic effect of synthetic CXCL12 and stromal cell-mediated protection of CLL cells from spontaneous apoptosis. Furthermore, we found that stromal cells protected CLL cells from chemotherapy-induced apoptosis. Treatment with CXCR4 antagonists resensitized CLL cells cultured with stromal cells to fludarabine-induced apoptosis. These findings demonstrate that CXCR4 blocking agents effectively antagonize CXCL12-induced migratory and signaling responses and stromal protection of CLL cells from spontaneous or fludarabine-induced apoptosis. As such, small molecular CXCR4 antagonists may have activity in the treatment of patients with this disease. (Blood. 2005;106:1824-1830)

Importance of PI3 Kinase Family for Crosstalk between Chronic Lymphocytic Leukemia B Cells and the Stromal Microenvironment: Therapeutic Implications.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1125-1125
Author(s):  
Matthias T.W. Niedermeier ◽  
Justyna Rawluk ◽  
Zachary Knight ◽  
Kevan Shokat ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Cell Migration ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Dominant Role ◽  
Lymphocytic Leukemia ◽  
Drug Induced ◽  
Cxcr4 Signaling ◽  
Induced Apoptosis

Abstract Nontumoral accessory cells such as marrow stromal cells (MSC) or nurselike cells (NLC), which constitute the leukemia microenvironment, constitutively secrete the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). CXCL12 transduces signals via its receptor CXCR4, which is expressed at high levels by Chronic Lymphocytic Leukemia (CLL) B cells. Via the CXCL12-CXCR4 axis, CLL cells migrate and adhere to stromal cells. Adhesion to stromal cells protects CLL cells from spontaneous and drug-induced apoptosis in a contact-dependent fashion. Signaling pathways regulating these processes in CLL B cells are largely unknown. Here, we examined the importance of phosphatidyl-inositide 3-kinases (PI3-K) for migration and viability of CLL B cells using non-specific and isoform-specific PI3-K inhibitors. The importance of PI3-K for migration of CLL cells to CXCL12 was determined by transwell chemotaxis and pseudoemperipolesis (PEP) assays. Inhibition of PI3-K resulted in a significant reduction of CLL cell migration in chemotaxis and PEP assays. In comparison to untreated CLL cells, Ly 294002 inhibited chemotaxis to 65 ± 4.6% of untreated controls. Using a panel of isoform-specific PI 3-K inhibitors (PI-103, PIK-90, IC87114, TGX-115, ZK-75), we observed inhibition of chemotaxis by the multi-targeted compounds PI-103 (51.4 ± 0.2%) and PIK-90 (57.5 ± 8.9%), whereas p110beta and delta inhibition had no effect. We conclude from this part of the study that PI3-kinases play an important role for CXCR4 signaling in CLL B cells, mediating migratory responses and protection from apoptosis. Experiments with inhibitors of PI3-K with higher target selectivity suggest a dominant role for the class I PI3-K p110alpha for migration in response to CXCL12. Because adhesion to stroma mediates protection from chemotherapeutic drugs, we tested PI3-K inhibitors alone and in combination with fludarabine in CLL-stroma co-cultures. Pre-treatment of CLL cells with the PI3-K inhibitors Ly 294002, PI-103, and PIK-90 resulted in a significant decrease in viability of CLL cells co-cultured with and without stroma. Moreover, PI3-K isoform specific inhibitors enhance the cytotoxicity of Fludarabine and partially reverse the protective effect of stromal cells on fludarabine-induced apoptosis. Collectively, this study establishes that PI3-Ks play an important role in CXCR4 signaling for CLL cell migration and adhesion to stromal cells. New, isoform-specific PI3-K inhibitors enhance the cytotoxicity of fludarabine in suspension cultures and in co-cultures with stromal cells. Therefore, the therapeutic potential of PI3-K inhibitors alone or in combination with fludarabine should further be investigated. Figure. Figure.

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.

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