In vitro assessment of the efficiency of the PIM‑1 kinase pharmacological inhibitor as a potential treatment for Burkitt's lymphoma

Background: Chromosomal translocations are causally related to the development of many tumors. In Burkitt's lymphoma, abnormalities involving the c-myc gene are essential. The CT-element of the c-myc promoter adopts non-B-conformation in vivo and in vitro, and therefore provides a potential fragile site. Methods: We have developed a LM-PCR-based approach to test if chromosomal breakpoints indeed cluster in this region. Results: Amplifying both, wild-type as well as the translocated c-myc gene by LM-PCR, it was shown that chromosomal breakpoints did not cluster within the CT-element. Conclusions: Therefore, the CT-element is not especially susceptible to the formation of breakpoints leading to chromosomal translocations in Burkitt's lymphoma.

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In vitro correlates of clinical response to methotrexate in acute leukaemia and Burkitt's lymphoma

British Journal of Cancer ◽

10.1038/bjc.1976.202 ◽

1976 ◽

Vol 34 (5) ◽

pp. 484-492 ◽

Cited By ~ 7

Author(s):

R A Bender ◽

W A Bleyer ◽

J C Drake ◽

J L Ziegler

Keyword(s):

Clinical Response ◽

Acute Leukaemia ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma

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537 Potent in vitro and in vivo anti-tumor activity of ITF2357 by modulation of c-myc related miRNA signature in human Burkitt's lymphoma

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(10)72244-8 ◽

2010 ◽

Vol 8 (7) ◽

pp. 171

Author(s):

R. Zappasodi ◽

M.V. Iorio ◽

A. Cavanè ◽

M. Magni ◽

G. Ruggiero ◽

...

Keyword(s):

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Mirna Signature ◽

Anti Tumor Activity

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Treatment with 177 lu-HH1 Increases CD20 Expression in Non-Hodgkin Lymphoma Cells in Vitro and In Vivo

Blood ◽

10.1182/blood.v126.23.3245.3245 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3245-3245

Author(s):

Ada H.V. Repetto-Llamazares ◽

Roy Hartvig Larsen ◽

Landsverk Kirsti ◽

Trond Stokke ◽

Bergthora Eiriksdottir ◽

...

Keyword(s):

Monoclonal Antibody ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Lymphoma Cells ◽

Employment Equity ◽

Cd20 Expression ◽

Equity Ownership ◽

Anti Cd20

Abstract Immunotherapy (IT) with the anti-CD20 monoclonal antibody rituximab in combination with chemotherapy has resulted in significantly improved response rate and survival in patients with various types of CD20 positive B-cell lymphoproliferative disorders. To be effective, rituximab depends on selective expression of a sufficient number of CD20 antigens per cell. Treatment with rituximab alone or in combination with chemotherapy can, however, result in disappearance of the CD20 expression, which may result in reduced clinical effect of subsequent CD20 targeted treatments. We have discovered that treatment of NHL in vitro and in vivo with the anti-CD37 antibody radionuclide conjugate (ARC) 177Lu-DOTA-HH1 (177Lu-HH1 or Betalutin™) results in an upregulation of the CD20 antigen expression, and therefore represents a rationale for a combination treatment with both agents. The in vitro expression of CD20 in Burkitt's Lymphoma, Daudi, cells 1-7 days after treatment with 177Lu-HH1 increased up to 120 % when compared with cells treated with unlabeled mAb, while Ramos (Burkitt's Lymphoma) and Rec-1 (Mantle Cell Lymphoma) cells showed 10 to 30 % increase, indicating a variation of the antigen upregulation in vitro with different cell lines. An upregulation of CD20 at the same order of magnitude was observed when cells where treated with similar absorbed radiation doses of external beam radiation. Treatment of nude mice with Ramos xenografts with 177Lu-HH1 resulted in a 3 times higher uptake of radiolabeled rituximab in tumor xenografts 5 days after start of treatment than in mice treated with unlabeled HH1 (p < 0.05) while uptake in normal organs was similar in both treatment groups (p > 0.05). SCID mice with intravenously injected Rec-1 cells were treated with NaCl, 100 mg rituximab, 40 MBq/kg 177Lu-HH1 or with the combination of 40 MBq/kg 177Lu-HH1 followed with 100 mg rituximab 5 days later. The combination of 177Lu-HH1 and rituximab resulted in significantly improved survival as compared with NaCl or rituximab alone, and a strong therapeutic gain as compared with 177Lu-HH1 alone (Table 1). In conclusion, 177Lu-HH1 treatment seems to improve uptake of rituximab and increase tumor suppression when used prior to anti-CD20 monoclonal antibody targeting in preclinical models. The reason for the upregulation of CD20 is probably related to the oxidative stress induced by the ARC-treatment, which will be evaluated in further studies. If the upregultation of CD20 is confirmed in clinical studies this effect could affect the way ARC and CD20 immunotherapy would be used in the future. Table 1. Therapy experiment groups and result Group Median ± SD Surviving fraction at the end of the study % Increase in symptom free survival compared to control NaCl + NaCl 64 ± 2 0.1 ---- NaCl + Rituximab 75 ± 10 0.3 15.4 177 Lu-HH1 + NaCl 92 ± 14 * 0.3 43.8 177 Lu-HH1 + Rituximab > 132 * 0.7 > 106.3 *Significantly different from NaCl + NaCl group (p < 0.01) Disclosures Repetto-Llamazares: Nordic Nanovector ASA: Employment, Equity Ownership. Larsen:Nordic Nanovector ASA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Stokke:Nordic nanovector ASA: Equity Ownership. Generalov:Nordic Nanovector ASA: Employment. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership.

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Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man.

Journal of Experimental Medicine ◽

10.1084/jem.173.1.147 ◽

1991 ◽

Vol 173 (1) ◽

pp. 147-158 ◽

Cited By ~ 191

Author(s):

M Rowe ◽

L S Young ◽

J Crocker ◽

H Stokes ◽

S Henderson ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Epstein Barr Virus ◽

Large Cell ◽

Burkitt’S Lymphoma ◽

Scid Mice ◽

Burkitt's Lymphoma ◽

Barr Virus ◽

Epstein Barr

When human peripheral blood lymphocytes (PBLs) from Epstein-Barr virus (EBV)-seropositive donors are injected intraperitoneally into SCID mice, EBV+ B cell tumors develop within weeks. A preliminary report (Mosier, D. E., R. J. Gulizia, S. M. Baird, D. D. Richman, D. B. Wilson, R. I. Fox, and T. J. Kipps, 1989. Blood. 74(Suppl. 1):52a) has suggested that such tumors resemble the EBV-positive malignancy, Burkitt's lymphoma. The present work shows that generally the human (hu) PBL-SCID tumors are distinct from Burkitt's lymphoma and instead resemble lymphoblastoid cell lines (LCLs) generated by EBV-infection of normal B cells in vitro in terms of: (a) their cell surface phenotype, with expression of B cell activation antigens and adhesion molecules, (b) normal karyotype, and (c) viral phenotype, with expression of all the transformation-associated EBV latent proteins and, in a minority of cells, productive cycle antigens. Indeed, in vitro-transformed LCLs also grow when inoculated into SCID mice, the frequency of tumor outgrowth correlating with the in vitro growth phenotype of the LCL which is itself determined by the identity of the transforming virus (i.e., type 1 or type 2 EBV). Histologically the PBL-derived hu-SCID tumors resemble the EBV+ large cell lymphomas that develop in immuno-suppressed patients and, like the human tumors, often present at multiple sites as individual monoclonal or oligoclonal foci. The remarkable efficiency of tumor development in the hu-SCID model suggests that lymphomagenesis involves direct outgrowth of EBV-transformed B cells without requirement for secondary genetic changes, and that selection on the basis of cell growth rate alone is sufficient to explain the monoclonal/oligoclonal nature of tumor foci. EBV+ large cell lymphoma of the immunosuppressed may arise in a similar way.

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HMG-I/Y, a New c-Myc Target Gene and Potential Oncogene

Molecular and Cellular Biology ◽

10.1128/mcb.20.15.5490-5502.2000 ◽

2000 ◽

Vol 20 (15) ◽

pp. 5490-5502 ◽

Cited By ~ 128

Author(s):

Lisa J. Wood ◽

Mita Mukherjee ◽

Christine E. Dolde ◽

Yi Xu ◽

Joseph F. Maher ◽

...

Keyword(s):

Target Gene ◽

Cellular Proliferation ◽

Neoplastic Transformation ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Protein Synthesis Inhibitor ◽

Synthesis Inhibitor ◽

Serum Stimulation

ABSTRACT The HMG-I/Y gene encodes the HMG-I and HMG-Y proteins, which function as architectural chromatin binding proteins important in the transcriptional regulation of several genes. Although increased expression of the HMG-I/Y proteins is associated with cellular proliferation, neoplastic transformation, and several human cancers, the role of these proteins in the pathogenesis of malignancy remains unclear. To better understand the role of these proteins in cell growth and transformation, we have been studying the regulation and function of HMG-I/Y. The HMG-I/Y promoter was cloned, sequenced, and subjected to mutagenesis analysis. A c-Myc–Max consensus DNA binding site was identified as an element important in the serum stimulation of HMG-I/Y. The oncoprotein c-Myc and its protein partner Max bind to this site in vitro and activate transcription in transfection experiments. HMG-I/Yexpression is stimulated by c-Myc in a Myc-estradiol receptor cell line in the presence of the protein synthesis inhibitor cycloheximide, indicating that HMG-I/Y is a direct c-Myc target gene.HMG-I/Y induction is decreased in Myc-deficient fibroblasts. HMG-I/Y protein expression is also increased in Burkitt's lymphoma cell lines, which are known to have increased c-Myc protein. Like Myc, increased expression of HMG-I protein leads to the neoplastic transformation of both Rat 1a fibroblasts and CB33 cells. In addition, Rat 1a cells overexpressing HMG-I protein form tumors in nude mice. Decreasing HMG-I/Y proteins using an antisense construct abrogates transformation in Burkitt's lymphoma cells. These findings indicate that HMG-I/Y is a c-Myc target gene involved in neoplastic transformation and a member of a new class of potential oncogenes.

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