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Original article

Concentration of cytokines (IL-4, IL-12, IFNγ) in the blood plasma and its association with lymphocyte apoptosis in patients suffering from chronic lymphocytic leukemia

Hristina Dejanović1, Danijela Jovanović2,3
  • Geriatrische Rehaklinik Sonthofen, Sonthofen, Germany
  • University Clinical Center Kragujevac, Kragujevac, Serbia
  • University of Kragujevac, Faculty of Medical Sciences, Department of Internal Medicine, Kragujevac, Serbia

ABSTRACT

Introduction: Chronic lymphocytic leukemia (CLL) is a malignant disease of hematopoietic tissue and is the most common leukemia in adults. For years, the dominant view was that in the pathogenesis of chronic lymphocytic leukemia, the basic mechanism of the origin and progression of the disease is disruption in apoptosis and prolonged survival of malignant lymphocytes.

Aim: The aim of our study is to determine the association between the percentage of apoptotic lymphocytes in the peripheral blood of patients suffering from chronic lymphocytic leukemia and the concentration of antiapoptotic cytokines (IL-4, IL-12, IFNγ) in the patients’ blood plasma.

Materials and methods: The study included 29 patients suffering from chronic lymphocytic leukemia (21 men and 8 women) who had not been on a chemotherapy regimen in the preceding 6 months. Clinical parameters (clinical stage of disease, presence of lymphadenopathy, splenomegaly), biochemical parameters (LDH), and the type and percentage of bone marrow infiltration were determined in all patients. The percentage of apoptotic lymphocytes and the concentration of cytokines (IL-4, IL-12, IFNγ) in the patients’ plasma were determined from the patients’ peripheral blood.

Results: In the studied group of patients, plasma concentration values of IL-4 = 121.42 pg/ml (62.44 – 180.40), IL-12 = 7.62 pg/ml (4.36 – 10.87), IFNγ = 31.45 pg/ml (18.35 – 44.56) were detected. In the cell population, less than 1% of apoptotic cells were detected, ranging from 0.03% to a maximum of 0.84%. The results show no correlation between the concentration of cytokines and the percentage of apoptotic lymphocytes in the patients’ peripheral blood, however, they show that Il-12 concentration positively correlates with the stage of the disease, as well as with the percentage of bone marrow infiltration by malignant lymphocytes (p < 0.001 or p = 0.028).

Conclusion: Plasma concentrations of IL-4, IL-12, IFNγ are not correlated with the percentage of apoptotic lymphocytes in the peripheral blood of patients with chronic lymphocytic leukemia. Interleukin-12 nevertheless shows a positive correlation in advanced disease.


INTRODUCTION

Chronic lymphocytic leukemia (CLL) is a malignant disease of hematopoietic tissue that results from the proliferation and accumulation of clones, small, seeminlgy mature, immunologically altered lymphocytes in the peripheral blood, bone marrow, lymph nodes, spleen, and other organs, and this is the most common leukemia in adult patients [1].

For years, the predominant view was that in the pathogenesis of chronic lymphocytic leukemia, the basic mechanism of the onset and progression of the disease lay in the disruption of apoptosis and in the prolonged survival of malignant lymphocytes [1]. Nowdays, it is known that the prolonged survival of lymphocytes is an important parameter in the pathogenesis of the disease, but that the progression of the disease also depends on the increased proliferation of the malignant clone [2],[3]. Prolonged survival of malignant lymphocytes is partly due to genetic changes within the cells themselves, and partly to external influences, such as cell-cell interactions in target tissues (bone marrow, lymph nodes) and circulating cytokines, which also play a role in inhibiting apoptosis [3],[4],[5],[6].

The aim of our study was to determine the association between the percentage of apoptotic lymphocytes in the peripheral blood of patients suffering from chronic lymphocytic leukemia and the expression of Bcl-2 in malignant lymphocytes, as well as the concentration of antiapoptotic cytokines (IL-4, IL-12, IFNγ) in the patients’ plasma. Also, the aim was to compare the analyzed parameters with the available clinical and laboratory parameters of the disease.

MATERIALS AND METHODS

The study was conducted at the Clinic for Hematology of the University Clinical Center Kragujevac, as a prospective study, in the period between October 2017 and February 2018. The study included 29 patients (21 male and 8 female patients) suffering from chronic lymphocytic leukemia, who had not received chemotherapy in the preceding 6 months. Clinical parameters (clinical stage of the disease, presence of lymphadenopathy, splenomegaly), biochemical parameters (lactate dehydrogenase - LDH), type and percentage of bone marrow infiltration (nodular, interstitial and diffuse), as well as blood count parameters were determined in all patients. Five milliliters of peripheral blood, with ETDA anticoagulant, were sampled at once from all patients.

The percentage of apoptotic lymphocytes was determined in the peripheral blood, and the concentration of IL-4, IL-12, and IFNγ was determined from the patients’ blood plasma using the microbeads technique, on a Beckman Coulter FC500 Flow Cytometer.

Whole blood cells were centrifuged at 3,000 rpm for 10 minutes, upon which the leukocyte precipitate was transferred to a test tube containing 2 ml of Lymphoprep and centrifuged for 22 minutes at 3,000 rpm. Upon isolation, cells were washed three times in PBS and resuspended in ice-cold binding buffer to a final concentration of 1,000,000 cells/ml. After that, 10 μl of FITC-labeled Annexin V and 20 μl of 7-AAD were added to100 μl of the working solution, and then incubated in the dark for 15 minutes. After incubation, the contents were resuspended in 400 μl of binding solution and analyzed on a flow cytometer at a maximum of up to 20,000 events, on a lymphocyte population determined on the FS/SS diagram. It is considered that Annexin V (-); 7-AAD (-) cells are viable, that Annexin V (+); 7-AAD (-) cells are in the early stage of apoptosis, that Annexin V (+); 7-AAD (+) cells are in the late stage of apoptosis, while Annexin V (-); 7-AAD (+) cells are necrotic cells. The percentage of early and late apoptosis, as well as necrosis, was determined using CXP Cytometer software. Statistical data processing was performed with commercial statistical software – SPSS, version 20.

RESULTS

Our study population consisted of 70% male patients and 30% female patients, of the average age of 66.9 years (range: 53 – 87 years). As to the clinical parameters, 41% of the patients had a lower clinical stage of the disease (Rai 0 and 1), 28% were in the intermediate stage (Rai 2), while 31% of the patients were in the advanced stage of disease (Rai 3 and 4 ). The majority of patients had palpable lymphadenopathy (about 60%), while the spleen was palpable in about 43% of patients. As far as bone marrow infiltration is concerned, it was, by virtue of the disease, present in all patients, but the percentage of infiltration varied from 25% – 95%. The average leukocyte count in patients was 70.6 ± 47.1 x 109 /l, while the LDH concentration was 427.5 ± 216.5 U/l. Other tested parameters are presented in Table 1.

Table 1. The percentage of apoptotic lymphocytes in peripheral blood and the concentration of the analyzed cytokines

p370

Although the percentage of cells in apoptosis was negatively correlated with the observed parameters (concentrations of IL-12, IFNγ and IL-4), there was no statistical significance (p > 0.05). When analyzing cells in individual stages of apoptosis (early apoptosis, late apoptosis and necrosis) statistical significance was also not determined. When the concentration of cytokines was compared with the presence of lymphadenopathy and an enlarged spleen, no correlation was also observed. However, all three cytokines showed a negative correlation with the percentage of bone marrow infiltration by lymphocytes (p = 0.028, p = 0.030, p = 0.042).

With regards to the comparison of the cytokine concentration with the disease stage in patients, IFNγ and IL-4 did not show a statistically significant association, while the Il-12 concentration showed a significant negative correlation with the disease stage of patients (p < 0.01). In patients with more advanced disease stages, lower values of the concentration of IL-12 were detected. The concentration of LDH in the serum showed a high degree of positive correlation with the stage of disease (p < 0.01).

DISCUSSION

Studies analyzing in vitro survival of lymphocytes in cultures taken from patients with chronic lymphocytic leukemia, unequivocally showed that cultivated malignant lymphocytes in monoculture had a higher degree of apoptosis than cultivated non-malignant B lymphocytes [7],[8], which led to the conclusion that inhibition of the apoptosis of lymphocytes in chronic lymphocytic leukemia is not an innate mechanism of the cell itself, but a consequence of the interaction of malignant cells with the protective microenvironment. Our study considered peripheral blood as one of the microenvironments wherein peripheral blood lymphocytes circulate, the concentration of cytokines (IL-12, IFNγ and IL-6) in peripheral blood, as well as the association of cytokines with the percentage of apoptotic cells and the progression of the disease.

Studies dealing with the in vitro effect of IL-12 showed that IL-12 inhibits the apoptosis of chronic lymphocytic leukemia cells and thus contributes to the progression of the disease [9], but that this effect is not potent enough when chronic lymphocytic leukemia lymphocytes are cultured only with IL-12, rather it shows its full potential in combination with other cytokines [10]. As an anti-inflammatory cytokine, IL-12 also exhibits an antitumor effect, therefore, its lower concentration may be associated with disease progression [11].

Recent studies also contribute to this theory, reporting that patients suffering from psoriatic arthritis who were treated with ustekinumab (IL-12 inhibitor) had a higher incidence of chronic lymphocytic leukemia. Amongst these studies is the one by Gediz et al., which is in agreement with our results showing that lower concentrations of IL-12 occur in patients with advanced disease [12]. On the other hand, Parfieńczyk et al. showed that the concentrations of IL-12 and of IL-6 were higher in patients suffering from CLL, but their study included only patients with lower stage of the disease [13].

Regarding IL-4 and IFNγ, our results linking the concentrations of these cytokines to parameters of apoptosis and disease progression did not show a direct association. These cytokines have, in fact, been studied to a greater extent in literature, and although the plasma concentrations themselves have not been shown to be statistically significant, the density of receptors for IFNγ and IL-4, both on the leukemic lymphocytes themselves as well as on other immune cells, indicate the shifting of the immune response from Th1 response to Th2 response, (increase in IL-4 and decrease in IFNγ receptors), which opens up enough room for gradual development of chronic lymphocytic leukemia [14],[15].

CONCLUSION

Plasma concentrations of IL-4, IL-12 and IFNγ are not correlated with the percentage of apoptotic lymphocytes in the peripheral blood of patients with chronic lymphocytic leukemia, but they are significantly negatively correlated with bone marrow infiltration by malignant lymphocytes. As a separate parameter, IL-12 is negatively correlated with the stage of the disease, which distinguishes it as an antiapoptotic cytokine that should be considered in the pathogenesis and course of chronic lymphocytic leukemia and included in further research in this area.

  • Conflict of interest:
    None declared.

Informations

Volume 4 No 4

December 2023

Pages 370-374
  • Keywords:
    chronic lymphocytic leukemia, apoptosis, cytokines
  • Received:
    27 November 2023
  • Revised:
    04 December 2023
  • Accepted:
    05 December 2023
  • Online first:
    25 December 2023
  • DOI:
  • Cite this article:
    Dejanović H, Jovanović D. Concentration of cytokines (IL-4, IL-12, IFNγ) in the blood plasma and its association with lymphocyte apoptosis in patients suffering from chronic lymphocytic leukemia. Serbian Journal of the Medical Chamber. 2023;4(4):368-72. doi: 10.5937/smclk4-47931
Corresponding author

Danijela Jovanović
Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac
30 Zmaj Jovina Street, 34000 Kragujevac, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


  • 1. Čolović M, Janković G. Maligne bolesti krvi. Beograd: Zavod za udžbenike i nastavna sredstva; 1999. p. 426.

    2. Marisavljević D, Mihaljević B, Elezović I, Popović S, Suvajdžić-Vuković N, Vujić D, i sar. Klinička hematologija. Beograd: Zavod za udžbenike i nastavna sredstva; 2012. p. 1300.

    3. Wjtowicz M, Woowiec D. Dysregulation of apoptosis and proliferation in CLL cells. In: Oppezzo P, editor. Chronic lymphocytic leukemia [Internet]. Rijeka, Croatia: InTech Europe; 2012. p. 37-62. Available from: http://dx.doi.org/10.5772/27127.

    4. Tangye SG, Raison RL. Human cytokines suppress apoptosis of leukaemic CD5+ B cells and preserve expression of bcl-2. Immunol Cell Biol. 1997 Apr;75(2):127-35. doi: 10.1038/icb.1997.17. [CROSSREF]

    5. Schuhknecht S, Duensing S, Dallmann I, Grosse J, Reitz M, Atzpodien J. Interleukin-12 inhibits apoptosis in chronic lymphatic leukemia (CLL) B cells. Cancer Biother Radiopharm. 2002 Oct;17(5):495-9. doi: 10.1089/108497802760804718. [CROSSREF]

    6. Buschle M, Campana D, Carding SR, Richard C, Hoffbrand AV, Brenner MK. Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia. J Exp Med. 1993 Jan 1;177(1):213-8. doi: 10.1084/jem.177.1.213. [CROSSREF]

    7. Đurđević P. Hronična limfocitna leukemija: apopotoza maligno izmenjenih limfocita i oksidativni stres [doktorska disertacija]. [Kragujevac]: Univerzitet u Kragujevcu, Medicinski fakultet u Kragujevcu; 2006.

    8. Jovanović D. Hronična limfocitna leukemija: prognostički markeri i apoptoza malignih limfocita periferne krvi i kostne srži [doktorska disertacija]. [Kragujevac]: Univerzitet u Kragujevcu, Fakultet medicinskih nauka u Kragujevcu; 2015. p. 138.

    9. Schuhknecht S, Duensing S, Dallmann I, Grosse J, Reitz M, Atzpodien J. Interleukin-12 inhibits apoptosis in chronic lymphatic leukemia (CLL) B cells. Cancer Biother Radiopharm. 2002 Oct;17(5):495-9. doi: 10.1089/108497802760804718. [CROSSREF]

    10. Ghamlouch H, Ouled-Haddou H, Damaj G, Royer B, Gubler B, Marolleau JP. A combination of cytokines rescues highly purified leukemic CLL B-cells from spontaneous apoptosis in vitro. PLoS One. 2013;8(3):e60370. doi: 10.1371/ journal.pone.0060370. [CROSSREF]

    11. Page MJ, Bester J, Pretorius E. Interleukin-12 and its procoagulant effect on erythrocytes, platelets and fibrin(ogen): the lesser known side of inflammation. Br J Haematol. 2018 Jan;180(1):110-7. doi: 10.1111/bjh.15020. [CROSSREF]

    12. Gediz F, Ugur MC, Turkmen M, Kobak S. Ustekinumab-induced chronic lymphocytic leukemia in a patient with psoriatic arthritis. Reumatologia. 2021;59(1):58-61. doi: 10.5114/reum.2021.102618. [CROSSREF]

    13. Parfieńczyk A, Kiersnowska-Rogowska B, Rogowski F. Stezenia interleukin 6 i 12 we krwi u chorych na przewlekła białaczke limfatyczna B-komórkowa [Interleukin-6 and interleukin-12 blood levels in patients with chronic B-cell lymphocytic leukemia]. Pol Merkur Lekarski. 2004 Feb;16(92):157-61.

    14. Bojarska-Junak A, Waldowska M, Woś J, Chocholska S, Hus I, Tomczak W, et al. Intracellular IL-4 and IFN-γ expression in iNKT cells from patients with chronic lymphocytic leukemia. Oncol Lett. 2018 Feb;15(2):1580-90. doi: 10.3892/ol.2017.7484. [CROSSREF]

    15. Zaki M, Douglas R, Patten N, Bachinsky M, Lamb R, Nowell P, et al. Disruption of the IFN-gamma cytokine network in chronic lymphocytic leukemia contributes to resistance of leukemic B cells to apoptosis. Leuk Res. 2000 Jul;24(7):611-21. doi: 10.1016/s0145-2126(00)00022-9. [CROSSREF]


REFERENCES

1. Čolović M, Janković G. Maligne bolesti krvi. Beograd: Zavod za udžbenike i nastavna sredstva; 1999. p. 426.

2. Marisavljević D, Mihaljević B, Elezović I, Popović S, Suvajdžić-Vuković N, Vujić D, i sar. Klinička hematologija. Beograd: Zavod za udžbenike i nastavna sredstva; 2012. p. 1300.

3. Wjtowicz M, Woowiec D. Dysregulation of apoptosis and proliferation in CLL cells. In: Oppezzo P, editor. Chronic lymphocytic leukemia [Internet]. Rijeka, Croatia: InTech Europe; 2012. p. 37-62. Available from: http://dx.doi.org/10.5772/27127.

4. Tangye SG, Raison RL. Human cytokines suppress apoptosis of leukaemic CD5+ B cells and preserve expression of bcl-2. Immunol Cell Biol. 1997 Apr;75(2):127-35. doi: 10.1038/icb.1997.17. [CROSSREF]

5. Schuhknecht S, Duensing S, Dallmann I, Grosse J, Reitz M, Atzpodien J. Interleukin-12 inhibits apoptosis in chronic lymphatic leukemia (CLL) B cells. Cancer Biother Radiopharm. 2002 Oct;17(5):495-9. doi: 10.1089/108497802760804718. [CROSSREF]

6. Buschle M, Campana D, Carding SR, Richard C, Hoffbrand AV, Brenner MK. Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia. J Exp Med. 1993 Jan 1;177(1):213-8. doi: 10.1084/jem.177.1.213. [CROSSREF]

7. Đurđević P. Hronična limfocitna leukemija: apopotoza maligno izmenjenih limfocita i oksidativni stres [doktorska disertacija]. [Kragujevac]: Univerzitet u Kragujevcu, Medicinski fakultet u Kragujevcu; 2006.

8. Jovanović D. Hronična limfocitna leukemija: prognostički markeri i apoptoza malignih limfocita periferne krvi i kostne srži [doktorska disertacija]. [Kragujevac]: Univerzitet u Kragujevcu, Fakultet medicinskih nauka u Kragujevcu; 2015. p. 138.

9. Schuhknecht S, Duensing S, Dallmann I, Grosse J, Reitz M, Atzpodien J. Interleukin-12 inhibits apoptosis in chronic lymphatic leukemia (CLL) B cells. Cancer Biother Radiopharm. 2002 Oct;17(5):495-9. doi: 10.1089/108497802760804718. [CROSSREF]

10. Ghamlouch H, Ouled-Haddou H, Damaj G, Royer B, Gubler B, Marolleau JP. A combination of cytokines rescues highly purified leukemic CLL B-cells from spontaneous apoptosis in vitro. PLoS One. 2013;8(3):e60370. doi: 10.1371/ journal.pone.0060370. [CROSSREF]

11. Page MJ, Bester J, Pretorius E. Interleukin-12 and its procoagulant effect on erythrocytes, platelets and fibrin(ogen): the lesser known side of inflammation. Br J Haematol. 2018 Jan;180(1):110-7. doi: 10.1111/bjh.15020. [CROSSREF]

12. Gediz F, Ugur MC, Turkmen M, Kobak S. Ustekinumab-induced chronic lymphocytic leukemia in a patient with psoriatic arthritis. Reumatologia. 2021;59(1):58-61. doi: 10.5114/reum.2021.102618. [CROSSREF]

13. Parfieńczyk A, Kiersnowska-Rogowska B, Rogowski F. Stezenia interleukin 6 i 12 we krwi u chorych na przewlekła białaczke limfatyczna B-komórkowa [Interleukin-6 and interleukin-12 blood levels in patients with chronic B-cell lymphocytic leukemia]. Pol Merkur Lekarski. 2004 Feb;16(92):157-61.

14. Bojarska-Junak A, Waldowska M, Woś J, Chocholska S, Hus I, Tomczak W, et al. Intracellular IL-4 and IFN-γ expression in iNKT cells from patients with chronic lymphocytic leukemia. Oncol Lett. 2018 Feb;15(2):1580-90. doi: 10.3892/ol.2017.7484. [CROSSREF]

15. Zaki M, Douglas R, Patten N, Bachinsky M, Lamb R, Nowell P, et al. Disruption of the IFN-gamma cytokine network in chronic lymphocytic leukemia contributes to resistance of leukemic B cells to apoptosis. Leuk Res. 2000 Jul;24(7):611-21. doi: 10.1016/s0145-2126(00)00022-9. [CROSSREF]

1. Čolović M, Janković G. Maligne bolesti krvi. Beograd: Zavod za udžbenike i nastavna sredstva; 1999. p. 426.

2. Marisavljević D, Mihaljević B, Elezović I, Popović S, Suvajdžić-Vuković N, Vujić D, i sar. Klinička hematologija. Beograd: Zavod za udžbenike i nastavna sredstva; 2012. p. 1300.

3. Wjtowicz M, Woowiec D. Dysregulation of apoptosis and proliferation in CLL cells. In: Oppezzo P, editor. Chronic lymphocytic leukemia [Internet]. Rijeka, Croatia: InTech Europe; 2012. p. 37-62. Available from: http://dx.doi.org/10.5772/27127.

4. Tangye SG, Raison RL. Human cytokines suppress apoptosis of leukaemic CD5+ B cells and preserve expression of bcl-2. Immunol Cell Biol. 1997 Apr;75(2):127-35. doi: 10.1038/icb.1997.17. [CROSSREF]

5. Schuhknecht S, Duensing S, Dallmann I, Grosse J, Reitz M, Atzpodien J. Interleukin-12 inhibits apoptosis in chronic lymphatic leukemia (CLL) B cells. Cancer Biother Radiopharm. 2002 Oct;17(5):495-9. doi: 10.1089/108497802760804718. [CROSSREF]

6. Buschle M, Campana D, Carding SR, Richard C, Hoffbrand AV, Brenner MK. Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia. J Exp Med. 1993 Jan 1;177(1):213-8. doi: 10.1084/jem.177.1.213. [CROSSREF]

7. Đurđević P. Hronična limfocitna leukemija: apopotoza maligno izmenjenih limfocita i oksidativni stres [doktorska disertacija]. [Kragujevac]: Univerzitet u Kragujevcu, Medicinski fakultet u Kragujevcu; 2006.

8. Jovanović D. Hronična limfocitna leukemija: prognostički markeri i apoptoza malignih limfocita periferne krvi i kostne srži [doktorska disertacija]. [Kragujevac]: Univerzitet u Kragujevcu, Fakultet medicinskih nauka u Kragujevcu; 2015. p. 138.

9. Schuhknecht S, Duensing S, Dallmann I, Grosse J, Reitz M, Atzpodien J. Interleukin-12 inhibits apoptosis in chronic lymphatic leukemia (CLL) B cells. Cancer Biother Radiopharm. 2002 Oct;17(5):495-9. doi: 10.1089/108497802760804718. [CROSSREF]

10. Ghamlouch H, Ouled-Haddou H, Damaj G, Royer B, Gubler B, Marolleau JP. A combination of cytokines rescues highly purified leukemic CLL B-cells from spontaneous apoptosis in vitro. PLoS One. 2013;8(3):e60370. doi: 10.1371/ journal.pone.0060370. [CROSSREF]

11. Page MJ, Bester J, Pretorius E. Interleukin-12 and its procoagulant effect on erythrocytes, platelets and fibrin(ogen): the lesser known side of inflammation. Br J Haematol. 2018 Jan;180(1):110-7. doi: 10.1111/bjh.15020. [CROSSREF]

12. Gediz F, Ugur MC, Turkmen M, Kobak S. Ustekinumab-induced chronic lymphocytic leukemia in a patient with psoriatic arthritis. Reumatologia. 2021;59(1):58-61. doi: 10.5114/reum.2021.102618. [CROSSREF]

13. Parfieńczyk A, Kiersnowska-Rogowska B, Rogowski F. Stezenia interleukin 6 i 12 we krwi u chorych na przewlekła białaczke limfatyczna B-komórkowa [Interleukin-6 and interleukin-12 blood levels in patients with chronic B-cell lymphocytic leukemia]. Pol Merkur Lekarski. 2004 Feb;16(92):157-61.

14. Bojarska-Junak A, Waldowska M, Woś J, Chocholska S, Hus I, Tomczak W, et al. Intracellular IL-4 and IFN-γ expression in iNKT cells from patients with chronic lymphocytic leukemia. Oncol Lett. 2018 Feb;15(2):1580-90. doi: 10.3892/ol.2017.7484. [CROSSREF]

15. Zaki M, Douglas R, Patten N, Bachinsky M, Lamb R, Nowell P, et al. Disruption of the IFN-gamma cytokine network in chronic lymphocytic leukemia contributes to resistance of leukemic B cells to apoptosis. Leuk Res. 2000 Jul;24(7):611-21. doi: 10.1016/s0145-2126(00)00022-9. [CROSSREF]


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