CD52

Gene Summary

Gene:CD52; CD52 molecule
Aliases: CDW52
Location:1p36
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:CAMPATH-1 antigen
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD52 (cancer-related)

Blatt K, Herrmann H, Hoermann G, et al.
Identification of campath-1 (CD52) as novel drug target in neoplastic stem cells in 5q-patients with MDS and AML.
Clin Cancer Res. 2014; 20(13):3589-602 [PubMed] Related Publications
PURPOSE: The CD52-targeted antibody alemtuzumab induces major clinical responses in a group of patients with myelodysplastic syndromes (MDS). The mechanism underlying this drug effect remains unknown.
EXPERIMENTAL DESIGN: We asked whether neoplastic stem cells (NSC) in patients with MDS (n = 29) or acute myelogenous leukemia (AML; n = 62) express CD52.
RESULTS: As assessed by flow cytometry, CD52 was found to be expressed on NSC-enriched CD34(+)/CD38(-) cells in 8/11 patients with MDS and isolated del(5q). In most other patients with MDS, CD52 was weakly expressed or not detectable on NSC. In AML, CD34(+)/CD38(-) cells displayed CD52 in 23/62 patients, including four with complex karyotype and del(5q) and one with del(5q) and t(1;17;X). In quantitative PCR (qPCR) analyses, purified NSC obtained from del(5q) patients expressed CD52 mRNA. We were also able to show that CD52 mRNA levels correlate with EVI1 expression and that NRAS induces the expression of CD52 in AML cells. The CD52-targeting drug alemtuzumab, was found to induce complement-dependent lysis of CD34(+)/CD38(-)/CD52(+) NSC, but did not induce lysis in CD52(-) NSC. Alemtuzumab also suppressed engraftment of CD52(+) NSC in NSG mice. Finally, CD52 expression on NSC was found to correlate with a poor survival in patients with MDS and AML.
CONCLUSIONS: The cell surface target Campath-1 (CD52) is expressed on NSC in a group of patients with MDS and AML. CD52 is a novel prognostic NSC marker and a potential NSC target in a subset of patients with MDS and AML, which may have clinical implications and may explain clinical effects produced by alemtuzumab in these patients.

Hoermann G, Blatt K, Greiner G, et al.
CD52 is a molecular target in advanced systemic mastocytosis.
FASEB J. 2014; 28(8):3540-51 [PubMed] Related Publications
Advanced systemic mastocytosis (SM) is an aggressive hematopoietic neoplasm with poor prognosis and short survival times. So far, no curative therapy is available for affected patients. We have identified the cell surface antigen CD52 (CAMPATH-1) as a molecular target expressed abundantly on the surface of primary neoplastic mast cells (MCs) in patients with advanced SM. In contrast, neoplastic MCs of patients with indolent SM and normal MCs expressed only low levels or did not express CD52. To study the mechanisms of CD52 expression and the value of this antigen as a potential therapeutic target, we generated a human MC cell line, designated MCPV-1, by lentiviral immortalization of cord blood-derived MC progenitor cells. Functional studies revealed that activated RAS profoundly promotes surface expression of CD52. The CD52-targeting antibody alemtuzumab induced cell death in CD52(+) primary neoplastic MCs obtained from patients with SM as well as in MCPV-1 cells. NSG mice xenotransplanted with MCPV-1 cells survived significantly longer after treatment with alemtuzumab (median survival: 31 d untreated vs. 46 d treated; P=0.0012). We conclude that CD52 is a novel marker and potential therapeutic target in neoplastic MCs in patients with advanced SM.

Geisler CH, van T' Veer MB, Jurlander J, et al.
Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL.
Blood. 2014; 123(21):3255-62 [PubMed] Related Publications
The randomized Haemato Oncology Foundation for Adults in The Netherlands 68 phase 3 trial compared front-line chemotherapy with chemotherapy plus the CD52 monoclonal antibody alemtuzumab for high-risk chronic lymphocytic leukemia, defined as at least 1 of the following: unmutated immunoglobulin heavy chain genes, deletion 17p or 11q, or trisomy 12. Fit patients were randomized to receive either 6 28-day cycles of oral FC chemotherapy (days 1 through 3: fludarabine 40 mg/m(2) per day and cyclophosphamide 250 mg/m(2) per day: n = 139) or FC plus subcutaneous alemtuzumab 30 mg day 1 (FCA, n = 133). FCA prolonged the primary end point, progression-free survival (3-year progression-free survival 53 vs 37%, P = .01), but not the secondary end point, overall survival (OS). However, a post hoc analysis showed that FCA increased OS in patients younger than 65 years (3-year OS 85% vs 76%, P = .035). FCA also increased the overall response rate (88 vs 78%, P = .036), and the bone marrow minimal residual disease-negative complete remission rate (64% vs 43%, P = .016). Opportunistic infections were more frequent following FCA, but without an increase in treatment related mortality (FCA: 3.8%, FC: 4.3%). FCA improves progression-free survival in high-risk chronic lymphocytic leukemia. As anticipated, FCA is more immunosuppressive than FC, but with due vigilance, does not lead to a higher treatment-related mortality. This study was registered at www.trialregister.nl as trial no. NTR529.

Huang PY, Best OG, Almazi JG, et al.
Cell surface phenotype profiles distinguish stable and progressive chronic lymphocytic leukemia.
Leuk Lymphoma. 2014; 55(9):2085-92 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is clinically heterogeneous. While some patients have indolent disease for many years, 20-30% will progress and ultimately die of their disease. CLL may be classified by the Rai or Binet staging system, mutational status of the immunoglobulin variable heavy-chain gene (IGVH), ZAP-70 overexpression, cytogenetic abnormalities (13q-, + 12, 11q-, 17p-) and expression of several cell surface antigens (CD38, CD49d) that correlate with risk of disease progression. However, none of these markers identify all cases of CLL at risk. In a recent review, we summarized those CD antigens known to correlate with the prognosis of CLL. The present study has identified surface profiles of CD antigens that distinguish clinically progressive CLL from slow-progressive and stable CLL. Using an extended DotScan(™) CLL antibody microarray (Version 3; 182 CD antibodies), and with refined analysis of purified CD19 + B-cells, the following 27 CD antigens were differentially abundant for progressive CLL: CD11a, CD11b, CD11c, CD18, CD19, CD20 (two epitopes), CD21, CD22, CD23, CD24, CD25, CD38, CD40, CD43, CD45, CD45RA, CD52, CD69, CD81, CD84, CD98, CD102, CD148, CD180, CD196 and CD270. The extensive surface profiles obtained provide disease signatures with an accuracy of 79.2%, a sensitivity of 83.9% and a specificity of 72.5% that could provide the basis for a rapid test to triage patients with CLL according to probability of clinical progression and potential earlier requirement for treatment.

Park J, Bae EK, Lee C, et al.
Establishment and characterization of bortezomib-resistant U266 cell line: constitutive activation of NF-κB-mediated cell signals and/or alterations of ubiquitylation-related genes reduce bortezomib-induced apoptosis.
BMB Rep. 2014; 47(5):274-9 [PubMed] Free Access to Full Article Related Publications
Bortezomib has been known as the most promising anti-cancer drug for multiple myeloma (MM). However, recent studies reported that not all MM patients respond to bortezomib. To overcome such a stumbling-block, studies are needed to clarify the mechanisms of bortezomib resistance. In this study, we established a bortezomib-resistant cell line (U266/velR), and explored its biological characteristics. The U266/velR showed reduced sensitivity to bortezomib, and also showed crossresistance to the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation, known as stem-like feature, compared to parental U266 cells. U266/velR showed relatively less inhibitory effect of prosurvival NF-κB signaling by bortezomib. Further analysis of RNA microarray identified genes related to ubiquitination that were differentially regulated in U266/velR. Moreover, the expression level of CD52 in U266 cells was associated with bortezomib response. Our findings provide the basis for developing therapeutic strategies in bortezomib-resistant relapsed and refractory MM patients.

Gorin NC, Isnard F, Garderet L, et al.
Administration of alemtuzumab and G-CSF to adults with relapsed or refractory acute lymphoblastic leukemia: results of a phase II study.
Eur J Haematol. 2013; 91(4):315-21 [PubMed] Related Publications
The outlook for adults with refractory and relapsed acute lymphocytic leukemia (ALL) is poor. CD52 is expressed in most patients with ALL. Alemtuzumab is an anti-CD52 humanized monoclonal antibody. This phase II study assessed the efficacy of alemtuzumab combined with granulocyte-colony stimulating factor (G-CSF) to boost antibody-dependent cell cytotoxicity mediated by neutrophils. Twelve patients with relapsed (n = 11) or refractory (n = 1) ALL, including four relapses postallogeneic stem cell transplantation, were treated and monitored between October 2006 and January 2011. Patients received 1 wk of alemtuzumab every other day at increasing doses of 3, 10, and 30 mg to test tolerance and 30 mg three times a week for 12-18 infusions. If in complete remission (CR), patients received maintenance therapy for 1 wk, every 2 months. G-CSF was administered at 5 μg/kg per day during alemtuzumab administration. The primary endpoint was disappearance of blast cells on a marrow aspirate. CD52 was expressed in all patients. Four patients reached CR. In one additional patient, clearance of blast cells was observed in peripheral blood but not in the marrow. The most frequent adverse events during course 1 of treatment were fever and chills (n = 3), skin rash (n = 3), and bronchospasm (n = 2). Tumor lysis syndrome was observed at treatment initiation in one patient who reached CR. All patients progressed within a few months and all but one died. The surviving patient is still alive after relapse and a second allogeneic stem cell transplantation. This study shows that in relapse/refractory ALL, alemtuzumab with G-CSF can produce good responses of short duration.

Bisig B, de Reyniès A, Bonnet C, et al.
CD30-positive peripheral T-cell lymphomas share molecular and phenotypic features.
Haematologica. 2013; 98(8):1250-8 [PubMed] Free Access to Full Article Related Publications
Peripheral T-cell lymphoma, not otherwise specified is a heterogeneous group of aggressive neoplasms with indistinct borders. By gene expression profiling we previously reported unsupervised clusters of peripheral T-cell lymphomas, not otherwise specified correlating with CD30 expression. In this work we extended the analysis of peripheral T-cell lymphoma molecular profiles to prototypical CD30(+) peripheral T-cell lymphomas (anaplastic large cell lymphomas), and validated mRNA expression profiles at the protein level. Existing transcriptomic datasets from peripheral T-cell lymphomas, not otherwise specified and anaplastic large cell lymphomas were reanalyzed. Twenty-one markers were selected for immunohistochemical validation on 80 peripheral T-cell lymphoma samples (not otherwise specified, CD30(+) and CD30(-); anaplastic large cell lymphomas, ALK(+) and ALK(-)), and differences between subgroups were assessed. Clinical follow-up was recorded. Compared to CD30(-) tumors, CD30(+) peripheral T-cell lymphomas, not otherwise specified were significantly enriched in ALK(-) anaplastic large cell lymphoma-related genes. By immunohistochemistry, CD30(+) peripheral T-cell lymphomas, not otherwise specified differed significantly from CD30(-) samples [down-regulated expression of T-cell receptor-associated proximal tyrosine kinases (Lck, Fyn, Itk) and of proteins involved in T-cell differentiation/activation (CD69, ICOS, CD52, NFATc2); upregulation of JunB and MUM1], while overlapping with anaplastic large cell lymphomas. CD30(-) peripheral T-cell lymphomas, not otherwise specified tended to have an inferior clinical outcome compared to the CD30(+) subgroups. In conclusion, we show molecular and phenotypic features common to CD30(+) peripheral T-cell lymphomas, and significant differences between CD30(-) and CD30(+) peripheral T-cell lymphomas, not otherwise specified, suggesting that CD30 expression might delineate two biologically distinct subgroups.

Chen J, Pise-Masison CA, Shih JH, et al.
Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia.
Blood. 2013; 121(11):2029-37 [PubMed] Free Access to Full Article Related Publications
Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048.

Pettitt AR, Jackson R, Carruthers S, et al.
Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial.
J Clin Oncol. 2012; 30(14):1647-55 [PubMed] Related Publications
PURPOSE: In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination.
PATIENTS AND METHODS: Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS).
RESULTS: The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%.
CONCLUSION: Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.

Leskov I, Pallasch CP, Drake A, et al.
Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies.
Oncogene. 2013; 32(8):1066-72 [PubMed] Free Access to Full Article Related Publications
Although numerous mouse models of B-cell malignancy have been developed via the enforced expression of defined oncogenic lesions, the feasibility of generating lineage-defined human B-cell malignancies using mice reconstituted with modified human hematopoietic stem cells (HSCs) remains unclear. In fact, whether human cells can be transformed as readily as murine cells by simple oncogene combinations is a subject of considerable debate. Here, we describe the development of humanized mouse model of MYC/BCL2-driven 'double-hit' lymphoma. By engrafting human HSCs transduced with the oncogene combination into immunodeficient mice, we generate a fatal B malignancy with complete penetrance. This humanized-MYC/BCL2-model (hMB) accurately recapitulates the histopathological and clinical aspects of steroid-, chemotherapy- and rituximab-resistant human 'double-hit' lymphomas that involve the MYC and BCL2 loci. Notably, this model can serve as a platform for the evaluation of antibody-based therapeutics. As a proof of principle, we used this model to show that the anti-CD52 antibody alemtuzumab effectively eliminates lymphoma cells from the spleen, liver and peripheral blood, but not from the brain. The hMB humanized mouse model underscores the synergy of MYC and BCL2 in 'double-hit' lymphomas in human patients. Additionally, our findings highlight the utility of humanized mouse models in interrogating therapeutic approaches, particularly human-specific monoclonal antibodies.

Matutes E
Novel and emerging drugs for rarer chronic lymphoid leukaemias.
Curr Cancer Drug Targets. 2012; 12(5):484-504 [PubMed] Related Publications
Rarer chronic lymphoid leukaemias represent a challenge to the clinicians due to the limited information on their pathogenesis, difficulties on setting up prospective clinical trials and to their refractoriness to drugs used in the most common form of chronic lymphocytic leukaemia (CLL). In this review all these issues are addressed in three B-cell leukaemias: B-cell prolymphocytic leukaemia (B-PLL), hairy cell leukaemia (HCL) and HCL-variant and three T-cell leukaemias: T-cell prolymphocytic leukaemia (T-PLL), T-cell large granular lymphocytic leukaemia (T-cell LGLL) and adult T-cell leukaemia lymphoma (ATLL). Data will be presented on the natural history, current therapies and emerging drugs potentially useful in the treatment of patients with these leukaemias. Emphasis is made on: 1- the novel agents targeting a variety of B and T-cell antigens expressed on the surface of the leukaemic cells; these are either unconjugated monoclonal antibodies (McAb) such as Rituximab (anti-CD20), the second and third generation of anti-CD20 McAbs, Alemtuzumab (anti-CD52), Siplizumab (anti-CD2), Daclizumab (anti-CD25) and KW-0761, an anti-chemokine receptor 4 (CCR4) or McAbs conjugated to toxins such as CD22 linked to the pseudomonas exotoxin or radiolabelled McAb; 2- the use of new purine nucleosides such as nelarabine and 3- agents targeting deregulated genes in the leukaemic cells from these diseases such as the Poly (ADP-ribose) polymerase (PARP) Olarapib in T-PLL with deregulation of the ataxia telangiectasia mutated (ATM) gene. Data of phase I and II clinical studies with these agents as well as the potential and current use of other drugs are outlined.

Bisig B, Gaulard P, de Leval L
New biomarkers in T-cell lymphomas.
Best Pract Res Clin Haematol. 2012; 25(1):13-28 [PubMed] Related Publications
Peripheral T-cell lymphomas (PTCLs) are heterogeneous and uncommon malignancies characterized by an aggressive clinical course and a mostly poor outcome with current treatment strategies. The recent genome-wide molecular characterization of several entities has provided novel insights into their pathobiology and led to the identification of new biomarkers with diagnostic, prognostic or therapeutic implications for PTCL patients. Cell lineage and differentiation antigens (markers of γδ or NK lineage, of cytotoxicity, of follicular helper T cells) reflect the tumour's biological behaviour, and their detection in tissue samples may refine the diagnostic and prognostic stratification of the patients. Previously unrecognized gene rearrangements are being discovered (ITK-SYK translocation, IRF4/MUM1 and DUSP22 rearrangements), and may serve as diagnostic genetic markers. Deregulated molecules within oncogenic pathways (NF-κB, Syk, PDGFRα) and immunoreactive cell-surface antigens (CD30, CD52) have been brought to the fore as potential targets for guiding the development of novel therapies.

Gerard LM, Xing K, Sherifi I, et al.
Adult hemophagocytic lymphohistiocytosis with severe pulmonary hypertension and a novel perforin gene mutation.
Int J Hematol. 2012; 95(4):445-50 [PubMed] Related Publications
Adult hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly hyperinflammatory syndrome presenting both diagnostic and therapeutic challenges. HLH may be primary, due to an underlying genetic abnormality, and/or secondary to infection, malignancy, or rheumatologic conditions. We describe a case of HLH-associated severe pulmonary hypertension paralleling Epstein-Barr virus (EBV) reactivation in a 52-year-old male in whom a novel perforin missense mutation was found (PRF1 1517C>T). Although intolerant of standard therapy (HLH-2004 protocol), a 6-week course of anti-CD52 (alemtuzumab) was associated with freedom-from-transfusion from weeks 4 to 13. However, 15 weeks after the onset of salvage therapy, he succumbed to polymicrobial sepsis despite treatment with prophylactic anti-infectives, with necropsy revealing disseminated blastomycosis and relapsed HLH. This case illustrates uncertainties in the relationships between pulmonary hypertension, a newly described PRF1 mutation, and possible pre-existing latent infectious risk factors (such as EBV or Blastomyces) in the pathogenesis and therapeutic perils of adult HLH.

Nguyen TH, Havari E, McLaren R, et al.
Alemtuzumab induction of intracellular signaling and apoptosis in malignant B lymphocytes.
Leuk Lymphoma. 2012; 53(4):699-709 [PubMed] Related Publications
The molecular changes induced by alemtuzumab following binding of CD52 on B tumor cells were investigated. Alemtuzumab alone had no detectable impact on cell signaling but cross-linking of alemtuzumab on the surface of B tumor lines with anti-human Fc antibodies induced a transient Ca(2+) flux followed by phosphorylation of several kinases involved in stress and survival pathways, and expression of associated proteins including TNF-α. Cross-linking of alemtuzumab also induced capping and caspase-dependent apoptosis of the tumor lines. When using primary cells from B-CLL patients, alemtuzumab alone was capable of inducing protein phosphorylation and apoptosis through the cross-linking of alemtuzumab by FcγRIIb receptors on B-CLL cells. Apoptosis was prevented by blocking of FcγRIIb receptors with anti-CD32 antibody. Overall, our results indicate that cross-linking of alemtuzumab on B tumor cells can occur naturally through Fc receptor interaction and leads to the activation of specific cellular pathways and induction of apoptosis.

Saito Y, Nakahata S, Yamakawa N, et al.
CD52 as a molecular target for immunotherapy to treat acute myeloid leukemia with high EVI1 expression.
Leukemia. 2011; 25(6):921-31 [PubMed] Related Publications
Ecotropic viral integration site 1 (EVI1) is an oncogenic transcription factor in human acute myeloid leukemia (AML) with chromosomal alterations at 3q26. Because a high expression of EVI1 protein in AML cells predicts resistance to chemotherapy with a poor outcome, we have searched for molecular targets that will treat these patients with AML. In this study, we determined that CD52, which is mainly expressed on lymphocytes, is highly expressed in most cases of AML with a high EVI1 expression (EVI1(High)). CAMPATH-1H, a humanized monoclonal antibody against CD52, has been used to prevent graft-versus-host disease and treat CD52-positive lymphoproliferative disorders. Here, we investigated the antitumor effect of CAMPATH-1H on EVI1(High) AML cells. CAMPATH-1H significantly inhibited cell growth and induced apoptosis in CD52-positive EVI1(High) leukemia cells. Furthermore, CAMPATH-1H induced complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity against CD52-positive EVI1(High) leukemia cells. After an intravenous injection of CAMPATH-1H into NOD/Shi-scid/IL-2Rγ;null mice with subcutaneous engraftment of EVI1(High) leukemia cells, tumor growth rates were significantly reduced, and the mice survived longer than those in the phosphate-buffered saline-injected control group. Thus, CAMPATH-1H is a potential therapeutic antibody for the treatment of patients with EVI1(High) leukemia.

Savage KJ, Ferreri AJ, Zinzani PL, Pileri SA
Peripheral T-cell lymphoma--not otherwise specified.
Crit Rev Oncol Hematol. 2011; 79(3):321-9 [PubMed] Related Publications
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) does correspond to a heterogeneous group of nodal and extranodal mature T-cell lymphomas, with a low prevalence in Western countries. PTCL-NOS accounts for about 25% of all PTCL, which represent over 15% of all lymphomas. In the lymph node, PTCL-NOS shows paracortical or diffuse infiltrates with effacement of the normal architecture, with a broad cytological spectrum and a frequently observed inflammatory background. Some morphological variants include: lymphoepithelioid or Lennert's type, T-zone, and follicular. PTCL-NOS is characterized by an aberrant T-cell phenotype, with frequent loss of CD5 and CD7. A CD4+/CD8- phenotype predominates in nodal cases. CD4/CD8 +/+ or -/- is at times seen, as is CD8, CD56 and cytotoxic granule expression. Ki-67 rate is typically high. TCR β-chain is usually expressed; TCR genes are most often clonally rearranged. PTCL-NOS typically occurs in adults (median age 55-60 years), with a higher prevalence in males. It presents more often as disseminated disease, occasionally with eosinophilia, pruritis or hemophagocytic syndrome. Patients often have B symptoms, generalized lymphadenopathy, bone marrow infiltration, and extranodal involvement, with high or high-intermediate IPI score in 50-70% of cases. Prognosis is poor, with a 5-year OS of 20-30%. Some variables, like ST2(L), CXCR5, CXCR3, EBV infection, cytotoxic granule expression, high proliferative index, NF-κB expression, were proposed as prognostic indicators, but the IPI score, and its variant called PIT, remains the most effective prognostic factor. Patients with PTCL-NOS should be treated with anthracycline-containing chemotherapy, followed by radiotherapy in cases of stage I-II disease. This strategy is associated with an overall response rate higher than 60%, but the 5-year overall survival is only 20-30%. Upfront high-dose chemotherapy supported by autologous or allogeneic SCT is an investigational approach, with a 4-year overall survival of about 40%. Patients with chemosensitive relapse respond favorably to high-dose chemotherapy and ASCT, with long-term survival rates of 35-45%. Graft-versus-lymphoma effect following allogeneic SCT has been observed; and reduced intensity conditioning emerges as an attractive strategy for frail patients. Most patients with PTCL-NOS are enrolled in prospective trials to explore new approaches, and new agents, like gemcitabine, alemtuzumab and pralatrexate, are being investigated.

Querfeld C, Mehta N, Rosen ST, et al.
Alemtuzumab for relapsed and refractory erythrodermic cutaneous T-cell lymphoma: a single institution experience from the Robert H. Lurie Comprehensive Cancer Center.
Leuk Lymphoma. 2009; 50(12):1969-76 [PubMed] Related Publications
We present the results of an open-label clinical trial and the clinical use of alemtuzumab in 19 heavily pretreated patients with advanced erythrodermic cutaneous T-cell lymphomas (CTCL) (erythrodermic mycosis fungoides and Sézary syndrome). Ten patients received alemtuzumab intravenously using an escalating dose regimen with a final dose of 30 mg three times weekly for 4 weeks followed by subcutaneous administration for 8 weeks. Nine patients were treated with only the SQ or IV dosing. The overall response rate was 84%, with 9 (47%) complete and 7 (37%) partial remissions. The median follow-up was 24 months (range, 6 to 62+ months). Median overall survival was 41 months whereas median progression free survival was 6 months. Minimal residual disease by T-cell gene rearrangement studies was detected in 11 patients who achieved complete response and partial response. Toxicities included myelosuppression and infections; however, the majority of side effects were of Grade 2 in severity and transient. One patient was diagnosed with a concurrent lymphoma (mantle cell lymphoma) 6 months after completing alemtuzumab therapy. Alemtuzumab is particularly effective in patients with erythrodermic CTCL with acceptable toxicities. Combined strategies with alemtuzumab may achieve molecular remissions with longer response durations.

Mohan SR, Clemente MJ, Afable M, et al.
Therapeutic implications of variable expression of CD52 on clonal cytotoxic T cells in CD8+ large granular lymphocyte leukemia.
Haematologica. 2009; 94(10):1407-14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: T-cell large granular lymphocytic leukemia is a clonal proliferation of cytotoxic T-lymphocytes which often results in severe cytopenia. Current treatment options favor chronic immunosuppression. Alemtuzumab, a humanized monoclonal antibody against glycophosphatidylinositol-anchored CD52, is approved for patients refractory to therapy in other lymphoid malignancies.
DESIGN AND METHODS: We retrospectively examined treatment outcomes in 59 patients with CD8+ T-cell large granular lymphocytic leukemia, 41 of whom required therapy. Eight patients with severe refractory cytopenia despite multiple treatment regimens had been treated with subcutaneous alemtuzumab as salvage therapy. Flow cytometry was used to monitor expression of glycophosphatidylinositol-anchored CD52, CD55, and CD59 as well as to characterize T-cell clonal expansions by T-cell receptor variable beta-chain (Vbeta) repertoire.
RESULTS: Analysis of the effects of alemtuzumab revealed remissions with restoration of platelets in one of one patient, red blood cell transfusion independence in three of five patients and improvement of neutropenia in one of three, resulting in an overall response rate of 50% (4/8 patients). Clonal large granular lymphocytes exhibited decreased CD52 expression post-therapy in patients refractory to treatment. Samples of large granular lymphocytes collected prior to therapy also unexpectedly had a significant proportion of CD52-negative cells while a healthy control population had no such CD52 deficiency (p=0.026).
CONCLUSIONS: While alemtuzumab may be highly effective in large granular lymphocytic leukemia, prospective serial monitoring for the presence of CD52-deficient clonal cytotoxic T-lymphocytes should be a component of clinical trials investigating the efficacy of this drug. CD52 deficiency may explain lack of response to alemtuzumab, and such therapy may confer a survival advantage to glycophosphatidylinositol-negative clonal cytotoxic T-lymphocytes.

Zwick C, Preuss KD, Kubuschok B, et al.
Analysis of the antibody repertoire of patients with mantle cell lymphoma directed against mantle cell lymphoma-associated antigens.
Ann Hematol. 2009; 88(10):999-1003 [PubMed] Related Publications
Treatment results of mantle cell lymphomas (MCL) are not satisfactory and novel therapeutic approaches are warranted. Because "shared" tumor antigens like the group of cancer testis antigens are only rarely expressed in MCL, we applied serological analysis of antigens using recombinant expression cloning (SEREX) to a complementary DNA library derived from five cases of MCL using the sera of eight patients with MCL in order to define MCL-associated antigens that are immunogenic in these patients and might be used as vaccines for patients with MCL. Five antigens were detected by SEREX. Four of the five detected antigens (hypothetical protein FLK10233, recombining binding protein suppressor, a chromosomal sequence, and interleukin-1 receptor associated kinase) are also expressed by a wide spectrum of normal human cells, excluding their use as vaccines. In contrast, the expression of CD52, which was detected by antibodies in the serum of an MCL patient, is restricted to hematopoietic cells. Interestingly, anti-CD52 antibodies were detected in this patient before and >2 years after allogeneic transplantation, indicating that both the autologous as well as the allogeneic immune system recognized CD52. Since the anti-CD52 monoclonal antibody alemtuzumab has shown activity in MCL, a vaccine consisting of recombinant CD52 alone or combined with passive immunotherapy using alemtuzumab warrants furthers clinical and immunological evaluation in MCL.

Ahmed N, Leung KS, Rosenblatt H, et al.
Successful treatment of stem cell graft failure in pediatric patients using a submyeloablative regimen of campath-1H and fludarabine.
Biol Blood Marrow Transplant. 2008; 14(11):1298-304 [PubMed] Related Publications
Graft failure is a significant cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). We used a nonmyeloablative conditioning regimen consisting of the lympho-depleting humanized CD52-antibody Campath-1H and fludarabine to rescue 12 consecutive children age 9 months to 17 years with engraftment failure after initial myeloablative HSCT. Primary diagnoses included lymphohematologic malignancies (n=6), severe combined immunodeficiency syndrome (SCID) (n=4), and metabolic diseases (n=2). The same stem cell donor was used as for the primary graft: mismatched family member (n=7), matched unrelated donor (n=4), or matched related donor (n=1). The patients received doses of CD34+ cells that did not significantly differ from those used in the initial, failed transplant. At a median follow-up of 51 months (range, 4 to 84 months), 6 of 6 patients with nonmalignant diseases and 4 of 6 patients with malignancy were alive. Two patients died, 1 patient from pulmonary toxicity and 1 from relapse, at 51 days and 8 months posttransplantation, respectively. All 12 patients initially achieved sustained neutrophil engraftment and complete donor chimerism by day 28. Six patients received donor lymphocyte infusion (DLI) after "rescue" therapy to maintain donor chimerism. At 6 months, 4 patients had complete donor cell engraftment, 4 had 15% to 89% stable donor chimerism, and 3 had developed secondary graft failure. This conditioning regimen was generally well tolerated; 4 of the 12 patients never became neutropenic, and 9 never became thrombocytopenic. Only 1 patient developed graft-versus-host disease (GVHD; grade 1), and none had chronic GVHD. Thus, the regimen that we describe can be used with minimal toxicity to effectively overcome graft failure after myeloablative HSCT in children.

Agostinelli C, Piccaluga PP, Went P, et al.
Peripheral T cell lymphoma, not otherwise specified: the stuff of genes, dreams and therapies.
J Clin Pathol. 2008; 61(11):1160-7 [PubMed] Free Access to Full Article Related Publications
Peripheral T cell lymphomas (PTCL) account for about 12% of lymphoid tumours worldwide. Almost half show such morphological and molecular variability as to hamper any further classification, and to justify their inclusion in a waste-basket category termed "not otherwise specified (NOS)". The latter term is used for neoplasms with aggressive presentation, poor response to therapy and dismal prognosis. In contrast to B cell lymphomas, PTCL have been the subject of only a limited number of studies to elucidate their pathobiology and identify novel pharmacological approaches. Herewith, the authors revise the most recent contributions on the subject based on the experience they have gained in the extensive application of microarray technologies. PTCL/NOS are characterised by erratic expression of T cell associated antigens, including CD4 and CD52, which have recently been proposed as targets for ad hoc immunotherapies. PTCL/NOS also show variable Ki-67 marking, with rates >80% heralding a worse prognosis. Gene expression profiling studies have revealed that PTCL/NOS derive from activated T lymphocytes, more often of the CD4+ type, and bear a signature composed of 155 genes and related products that play a pivotal role in cell signalling transduction, proliferation, apoptosis and matrix remodelling. This observation seems to pave the way for the use of innovative drugs such as tyrosine kinase and histone deacetylase inhibitors whose efficacy has been proven in PTCL primary cell cultures. Gene expression profiling also allows better distinction of PTCL/NOS from angioimmunoblastic T cell lymphoma, the latter being characterised by follicular T helper lymphocyte derivation and CXCL13, PD1 and vascular endothelial growth factor expression.

Rizzo K, Stetler-Stevenson M, Wilson W, Yuan CM
Novel CD19 expression in a peripheral T cell lymphoma: A flow cytometry case report with morphologic correlation.
Cytometry B Clin Cytom. 2009; 76(2):142-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Peripheral T-cell lymphomas are uncommon lymphomas that show T-cell antigenic loss and clonal T-cell receptor (TCR) gene rearrangement. Rare cases of T-cell lymphomas with aberrant expression of CD20 have been described. However, CD19 coexpression in a mature T-cell neoplasm has not been reported.
METHODS: Histology, immunohistochemistry (IHC), and PCR for TCR gene rearrangement were performed on an excised lymph node specimen and a subsequent fine needle aspiration (FNA) of an additional lymph node. Flow cytometry (FC) was performed on FNA and peripheral blood specimen.
RESULTS: The lymph node's architecture was effaced by a diffuse atypical lymphoid proliferation that, by IHC, was positive for CD3, CD2, and CD43 and negative for CD4, CD5, CD8, TdT, CD1a, and B-cell-associated antigens PAX-5, CD20, and CD79a. A clonal TCR gene rearrangement was detected. FC was performed on a subsequent FNA, and peripheral blood specimen demonstrated an aberrant T-cell population with expression of CD2, CD3, CD27, TCR alpha/beta, CD52, CD38, CD45, and CD26 (partial expression) and negative for CD4, CD5, CD7, CD8, CD10, CD30, and CD56. The aberrant T-cell population also expressed bright CD19.
CONCLUSIONS: Using FC, we describe the first case of peripheral T-cell lymphoma with aberrant coexpression of CD19.

Boyd K, Dearden CE
Alemtuzumab in the treatment of chronic lymphocytic lymphoma.
Expert Rev Anticancer Ther. 2008; 8(4):525-33 [PubMed] Related Publications
Alemtuzumab was the first monoclonal antibody to be humanized, a process which embeds rodent sequence fragments in a human IgG framework. The antibody target is CD52, an antigen expressed on normal lymphocytes as well as many T- and B-cell neoplasms. It therefore has a potential broad application across a spectrum of B- and T-cell malignancies as well as use as an immunosuppressant drug in, for example, bone marrow transplantation. The original licensing in the USA and Europe was for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). However, recent trials using alemtuzumab as a first-line agent for CLL have shown superior response rates compared with traditional alkylator therapy and this has led to US FDA approval for first-line treatment for CLL. It seems to be particularly useful in patients with CLL who have deletion of the TP53 tumor suppressor gene, a subset of disease that responds poorly to other currently available chemotherapeutics.

Lapalombella R, Zhao X, Triantafillou G, et al.
A novel Raji-Burkitt's lymphoma model for preclinical and mechanistic evaluation of CD52-targeted immunotherapeutic agents.
Clin Cancer Res. 2008; 14(2):569-78 [PubMed] Related Publications
PURPOSE: To date, efforts to study CD52-targeted therapies, such as alemtuzumab, have been limited due to the lack of stable CD52 expressing transformed B-cell lines and animal models. We describe generation and utilization of cell lines that stably express CD52 both in vitro and in vivo.
EXPERIMENTAL DESIGN: By limiting dilution, we have established several clones of Raji-Burkitt's lymphoma cell line that express surface CD52. Immunophenotype and cytogenetic characterization of these clones was done. In vivo usefulness of the CD52(high) cell line to evaluate the therapeutic efficacy of CD52-directed antibody was investigated using a SCID mouse xenograft model.
RESULTS: Stable expression of CD52 was confirmed in cells cultured in vitro up to 52 weeks of continuous growth. The functional integrity of the expressed CD52 molecule was shown using alemtuzumab, which induced cytotoxic effects in vitro in the CD52(high) but not the CD52(low) clone. Compared with control antibody, alemtuzumab treatment in CD52(high) inoculated mice resulted in significantly increased median survival. Comparable levels of CD52-targeted direct cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cytotoxicity and anti-CD52 immunoliposome-mediated delivery of synthetic oligodeoxyribo nucleotides in CD52(high) clone and primary B-chronic lymphocytic leukemia cells implicated potential in vivo application of this model for evaluation of CD52-targeted antibody and immunoliposomes encapsulating therapeutic agents.
CONCLUSIONS: These results show the in vitro utility of the cloned Raji cell lines that stably express high levels CD52. The disseminated leukemia-lymphoma mouse model described herein using these stable cell lines can serve as an excellent system for in vivo therapeutic and mechanistic evaluation of existing and novel antibodies directed against CD52 molecule.

Piccaluga PP, Agostinelli C, Righi S, et al.
Expression of CD52 in peripheral T-cell lymphoma.
Haematologica. 2007; 92(4):566-7 [PubMed] Related Publications
Peripheral T-cell lymphoma unspecified (PTCL/U) is a rare tumor characterized by poor treatment response and a dismal prognosis. We studied CD52 expression in 97 PTCL/U cases by immunohistochemistry on tissue-microarrays. Furthermore, CD52 gene expression was studied in 28 cases for which RNA was available. We found that CD52 is expressed in approximately 40% of PTCLs/U at the same level as in normal T-lymphocytes. Although other factors may play a role in the in vivo response to alemtuzumab, an anti-CD52 monoclonal antibody, the estimation of CD52 expression may provide a rationale for the selection of patients with a higher probability of treatment response.

Winkler D, Döhner H, Stilgenbauer S
Genetics, gene expression, and targeted therapies in chronic lymphocytic leukemia.
Curr Drug Targets. 2006; 7(10):1313-27 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) represents the most common leukemia among adults in the Western countries. CLL is a remarkably diverse disorder following an extremely variable clinical course. Some patients have an indolent disease that may never require treatment. In others a progressive clinical course is rapidly fatal. CLL affects mainly elderly individuals, but about a third of patients are less than 60 years of age at diagnosis. Traditionally, the therapeutic procedures were aimed at palliation, but over the recent years highly effective and potentially curative approaches such as combined antibody-chemotherapy and autologous or allogeneic stem cell transplantation have been developed. In parallel there has been progress in the understanding of pathogenesis and outcome prediction. The cornerstones to estimate prognosis are the clinical staging systems of Rai and Binet. To refine outcome prediction for individual patients there has been intensive work on biological factors of potential prognostic relevance. Among these, the genetic characteristics of the CLL cells that can be divided into genomic aberrations and the mutation status of the variable segments of immunoglobulin-heavy chain genes (VH) have attained considerable importance. In addition, data on gene expression of CLL cells are accumulating which further characterize the CLL subgroups. In this context, the expression of ZAP-70 has been recognized a useful surrogate marker to predict the VH mutation status and outcome of CLL patients. At present, targeted therapies are focused on humanized antibodies that bind proteins expressed on the surface of CLL cells. The most prominent agents of these are the anti-CD52 antibody alemtuzumab and the anti-CD20 antibody rituximab, which are currently being tested in clinical trials. To identify CLL-specific gene expression products as candidates for targeted therapies will be an important part of CLL research in the next years.

Rawstron AC, Laycock-Brown G, Hale G, et al.
CD52 expression patterns in myeloma and the applicability of alemtuzumab therapy.
Haematologica. 2006; 91(11):1577-8 [PubMed] Related Publications
Alemtuzumab has been proposed as a therapeutic agent in myeloma. CD52 was detected on plasma cells in 46/106 patients but levels were 30-fold lower than on alemtuzumab-responsive cells (n=138) and 8-fold lower than on alemtuzumab-resistant cells (n=57). The data suggest that myeloma plasma cells are unlikely to be depleted by alemtuzumab in most patients.

Rezvany MR, Tehrani MJ, Karlsson C, et al.
Reconstitution of the T-cell repertoire following treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with B-cell chronic lymphocytic leukaemia.
Br J Haematol. 2006; 135(4):475-85 [PubMed] Related Publications
In this pilot study, T-cell receptor B-variable (TCR-BV) gene usage in CD4 and CD8 T cells was assessed, by real-time polymerase chain reaction, as well as complementarity-determining region 3 (CDR3)-length polymorphism, before and after therapy in five patients with B-cell chronic lymphocytic leukaemia who received alemtuzumab (anti-CD52 monoclonal antibody) as first-line therapy. A decline in expression of most BV family genes in both CD4 and CD8 T cells was observed after alemtuzumab treatment, which was followed by a gradual increase in most BV families during long-term follow-up. After treatment, CDR3-length polymorphism showed an even more restricted pattern in CD4 T cells compared with pretreatment, with a shift towards a monoclonal/oligoclonal pattern. The clonally restricted pattern was significantly reduced in CD4 (P < 0.01) but not in CD8 T cells. This was followed by a gradual increase in the number of peaks within the CDR3 region of the different TCR-BV families, i.e. a polyclonal repertoire, during long-term follow-up. A restricted CDR3 pattern became even more restricted after treatment, but normalised during unmaintained follow-up. These results indicate that perturbations in the T-cell alterations following alemtuzumab are complex and include not only changes in CD4/CD8 T-cell numbers but also a highly restricted T-cell repertoire especially in CD4 T cells.

Hahtola S, Tuomela S, Elo L, et al.
Th1 response and cytotoxicity genes are down-regulated in cutaneous T-cell lymphoma.
Clin Cancer Res. 2006; 12(16):4812-21 [PubMed] Related Publications
PURPOSE: Increased production of Th2 cytokines characterizes Sezary syndrome, the leukemic form of cutaneous T-cell lymphomas (CTCL). To identify the molecular background and to study whether shared by the most common CTCL subtype, mycosis fungoides, we analyzed the gene expression profiles in both subtypes.
EXPERIMENTAL DESIGN: Freshly isolated cells from 30 samples, representing skin, blood, and enriched CD4(+) cell populations of mycosis fungoides and Sezary syndrome, were analyzed with Affymetrix (Santa Clara, CA) oligonucleotide microarrays, quantitative PCR, or immunohistochemistry. The gene expression profiles were combined with findings of comparative genomic hybridization of the same samples to identify chromosomal changes affecting the aberrant gene expression.
RESULTS: We identified a set of Th1-specific genes [e.g., TBX21 (T-bet), NKG7, and SCYA5 (RANTES)] to be down-regulated in Sezary syndrome as well as in a proportion of mycosis fungoides samples. In both Sezary syndrome and mycosis fungoides blood samples, the S100P and LIR9 gene expression was up-regulated. In lesional skin, IL7R and CD52 were up-regulated. Integration of comparative genomic hybridization and transcriptomic data identified chromosome arms 1q, 3p, 3q, 4q, 12q, 16p, and 16q as likely targets for new CTCL-associated gene aberrations.
CONCLUSIONS: Our findings revealed several new genes involved in CTCL pathogenesis and potential therapeutic targets. Down-regulation of a set of genes involved in Th1 polarization, including the major Th1-polarizing factor, TBX21, was for the first time associated with CTCL. In addition, a plausible explanation for the proliferative response of CTCL cells to locally produced interleukin-7 was revealed.

Magro CM, Morrison CD, Heerema N, et al.
T-cell prolymphocytic leukemia: an aggressive T cell malignancy with frequent cutaneous tropism.
J Am Acad Dermatol. 2006; 55(3):467-77 [PubMed] Related Publications
BACKGROUND: T-cell prolymphocytic leukemia (T-PLL), formerly categorized as T-cell chronic lymphocytic leukemia, is a rare and aggressive hematologic malignancy. Although the skin is characteristically involved, it is not a well-recognized entity in the dermatologic literature.
METHODS: Six cases of cutaneous T-PLL are presented from a clinical, light microscopic, and phenotypic perspective.
RESULTS: The patient population comprised 2 women and 4 men, with a mean age of 69.8 years. The disease was associated in all with skin involvement with facial preference; edema, purpura, and lesional symmetry were characteristic. The skin biopsies demonstrated a largely non-epidermotropic angiocentric lymphocytic infiltrate with accompanying hemorrhage. The cells showed irregular- to reniform-shaped nuclei with small nucleoli and eosinophilic rims of cytoplasm. Phenotypic studies revealed three prevailing profiles: CD4 dominant in 4, CD8 dominant in one, and co-expression of CD4 and CD8 in one. CD3 loss was seen in one case. All expressed T-cell leukemia 1 (TCL-1) and CD7; cutaneous lymphocyte antigen expression was discernible in a dot-like perinuclear array. All cases tested excluding one expressed TCL-1 and CD52. In two cases tested, T-cell receptor beta rearrangements were observed. Cytogenetic studies demonstrated a paracentromeric chromosome 14 inversion. Polysomy 8 and MYC amplification was seen in one case, manifesting an aggressive clinical course. Four patients died from their disease within 18 months of diagnosis.
LIMITATIONS: Cytogenetic MYC amplification, FISH, and TCR beta studies were conducted on each of 2 cases, respectively, due to limitations of tissue block samples and/or peripheral blood. cMYC translocation studies were conducted on 3 of the 6 cases, again due to limitations imposed by the tissue samples on the cases. The last case was recently diagnosed and, therefore, long-term follow-up is not possible.
CONCLUSION: T-PLL is a distinctive post-thymic T-cell malignancy with frequent cutaneous tropism. A diagnosis is possible in almost all cases based on characteristic clinical, light microscopic, phenotypic, and cytogenetic features. While a chromosome 14 inversion is highly characteristic, additional inherent cytogenetic differences, such as trisomy 8 with CMYC over-amplification, may account for some case to case variation in clinical course.

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