Philadelphia Chromosome Symposium: commemoration of the 50th anniversary of the discovery of the Ph chromosome.

This report summarizes highlights of the Philadelphia Chromosome Symposium: Past, Present and Future, held September 28, 2010, to commemorate the 50th anniversary of the discovery of the Philadelphia chromosome. The symposium sessions included presentations by investigators who made seminal contributions concerning the discovery and molecular characterization of the Ph chromosome and others who developed a highly successful therapy based on the specific molecular alteration observed in chronic myeloid leukemia. Additional presentations highlighted future opportunities for the design of molecularly targeted therapies for various types of cancer. Also included here are reminiscences connected with the discovery of the Ph chromosome by David Hungerford and Peter Nowell, the discovery that the abnormality arises from a chromosomal translocation, by Janet Rowley, and the cloning of the 9;22 translocation breakpoints by Nora Heisterkamp, John Groffen, and colleagues.

Trisomy 8 in an allogeneic stem cell transplant recipient representative of a donor-derived constitutional abnormality.

Trisomy 8 is a common cytogenetic abnormality in myeloid malignancies. It can also be present constitutionally and is associated with a wide range of phenotypes. We report a case of a 20-year-old woman with acute myelogenous leukemia associated with the 11q23/MLL translocation who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a healthy, unrelated 26-year-old female. Cytogenetics on a bone marrow biopsy and aspirate performed 71 days after transplant to evaluate pancytopenia identified trisomy 8 in 6 of 7 cells examined. The bone marrow was hypocellular but normal by morphology and flow cytometry. Fluorescent in situ hybridization (FISH) for the original 11q23/MLL translocation was negative. Chimerism analysis using multiplex polymerase chain reaction to amplify an informative short tandem repeat demonstrated 97% donor cells. These findings were confirmed by repeat bone marrow biopsies at Day 110 after transplant and 1 year after transplant. With resolution of comorbid illness, the patient's peripheral blood counts recovered and remained normal at 1 year after HSCT. FISH analysis of a cryopreserved sample of the donor graft showed trisomy 8 in 120 of 200 cells examined. This represents the first reported case of a person with constitutional trisomy 8 mosaicism serving as a stem cell donor. The case illustrates the importance of identifying donor-derived constitutional abnormalities to avoid the assumption that these cytogenetic abnormalities after HSCT are representative of malignant disease.

Sézary syndrome coexisting with B-cell chronic lymphocytic leukemia: case report and review of the literature.

INTRODUCTION: The simultaneous presentation of chronic B-cell lymphocytic leukemia (B-CLL) and cutaneous T-cell lymphoma (CTCL) is extremely rare. CASE REPORT: We describe a patient with B-CLL and Sézary syndrome (SS), an erythrodermic and leukemic variant of CTCL. Despite treatment, the SS progressed to involve internal organs and eventual death of the patient from sepsis. This is the first reported case of SS coexisting with chronic lymphocytic leukemia in which an anti-V beta 13.6 antibody was used to serially track changes in circulating neoplastic T cells vis-à-vis neoplastic B cells and to detect neoplastic T cells in ascitic fluid near the end of the patient's life. DISCUSSION: We speculate that the coexistence of B-CLL and CTCL is the result of an initiating genetic or epigenetic defect at the level of the common lymphoid stem cell that predisposes both B-cell and T-cell lineages to additional oncogenic changes at a more advanced stage of differentiation.

Discovery of the Philadelphia chromosome: a personal perspective.

Almost 50 years ago, David Hungerford and I noticed an abnormally small chromosome in cells from patients with chronic myelogenous leukemia (CML). This article is a personal perspective of the events leading to the discovery of this chromosome, which became known as the Philadelphia chromosome. As technology advanced over subsequent decades, the translocation resulting in the Philadelphia chromosome has been identified, its role in the development of CML has been confirmed, and a therapy directed against the abnormal protein it produces has shown promising results in the treatment of patients with CML.

A novel t(3;8)(q27;q24.1) simultaneously involving both the BCL6 and MYC genes in a diffuse large B-cell lymphoma.

Diffuse large B-cell lymphomas (DLBCLs) are a clinically and biologically heterogeneous group of hematologic malignancies. Specific genetic aberrations underlie some of this heterogeneity. These genetic events include distinct and separate translocations resulting in the dysregulated expression of either BCL6 protein with the t(3;14)(q27;q32) or c-MYC protein with the t(8;14)(q24;q32), as a consequence of the juxtaposition of these oncogenes with heterologous promoters or enhancers, such as those of the immunoglobulin heavy chain gene. Here, we report the case of a patient with DLBCL with a unique t(3;8)(q27;q24.1) that involves the BCL6 and MYC genes. We know of no previous report of this translocation in DLBCL, which simultaneously affects two key genes implicated in lymphomagenesis and may reflect a novel genetic mechanism in neoplastic transformation.

Heterogeneous abnormalities of CCND1 and RB1 in primary cutaneous T-Cell lymphomas suggesting impaired cell cycle control in disease pathogenesis.

Upregulation of cyclin D1/B-cell leukemia/lymphoma 1 (CCND1/BCL1) is present in most mantle cell lymphomas with the t(11;14)(q13;q32) translocation. However, little is known about the abnormalities of CCND1 and its regulator RB1 in primary cutaneous T-cell lymphomas (CTCL). We analyzed CCND and RB status in CTCL using fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), and Affymetrix expression microarray. FISH revealed loss of CCND1/BCL1 in five of nine Sézary syndrome (SS) cases but gain in two cases, and RB1 loss in four of seven SS cases. IHC showed absent CCND1/BCL1 expression in 18 of 30 SS, 10 of 23 mycosis fungoides (MF), and three of 10 primary cutaneous CD30+ anaplastic large-cell lymphoma (C-ALCL). Increased CCND1/BCL1 expression was seen in nine MF, seven C-ALCL, and six SS cases. Absent RB1 expression was detected in 8 of 12 MF and 7 of 9 SS cases, and raised RB1 expression in 7 of 8 C-ALCL. Affymetrix revealed increased gene expression of CCND2 in four of eight CTCL cases, CCND3 in three cases, and CDKN2C in two cases with a normal expression of CCND1 and RB1. These findings suggest heterogeneous abnormalities of CCND and RB in CTCL, in which dysregulated CCND and RB1 may lead to impaired cell cycle control.

Management of health-care--associated infections in the oncology patient.

Each year, 2.4 million patients in the United States develop health-care--associated infections (HAIs), requiring treatment at an annual cost of approximately $4.5 billion. HAI is the primary cause of death in approximately 30,000 patients and contributes to the death of 70,000 annually. Oncology patients are more susceptible than other patients to HAIs due to compromised immune systems, surgery (drains), invasive technology (catheters), and environmental factors. This paper will review each of these risk factors and discuss preventive steps such as a predictive index, antibiotic therapy, and infection control practices.

Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia with MLL translocations in infants and children.

An inactivating polymorphism at position 609 in the NAD(P)H:quinone oxidoreductase 1 gene (NQO1 C609T) is associated with an increased risk of adult leukemia. A small British study suggested that NQO1 C609T was associated with an increased risk of infant leukemias with MLL translocations, especially infant acute lymphoblastic leukemia (ALL) with t(4;11). We explored NQO1 C609T as a genetic risk factor in 39 pediatric de novo and 18 pediatric treatment-related leukemias with MLL translocations in the United States. Children with de novo B-lineage ALL without MLL translocations and a calculation of the expected genotype distribution in an ethnically matched population of disease-free subjects served as the comparison groups. Patients with de novo leukemias with MLL translocations were significantly more likely to be heterozygous at NQO1 C609T (odds ratio [OR] = 2.77, 95% confidence intervals [CI] 1.17-6.57; P =.02), and significantly more likely to have low/null NQO1 activity than patients with de novo B-lineage ALL without MLL translocations (OR = 2.47, 95% CI 1.08-5.68; P =.033). They were also significantly more likely to have low/null NQO1 activity than expected in an ethnically matched population of disease-free subjects (OR = 2.50, P =.02). Infants younger than 12 months old at diagnosis of leukemia with t(4;11) were most likely to have low/null NQO1 activity (OR > 10.0). Conversely, the distribution of NQO1 genotypes among patients with treatment-related leukemias with MLL translocations was not statistically different than in the comparison groups. The inactivating NQO1 polymorphism is associated with an increased risk of de novo leukemia with MLL translocations in infants and children.

Studies of normal and neoplastic lymphocytes.

This brief review encapsulates a nearly 50-year career in biomedical research, primarily studying human leukemias and lymphomas, but also involving normal lymphocytes. Early observations included the feasibility of bone marrow transplantation (and related problems with graft-vs.-host reactions); the mitogenic effect of phytohemagglutinin (and resultant human lymphocyte culture techniques); and early cytogenetic findings in human leukemias, both lymphocytic and myeloid (including the Philadelphia chromosome). Subsequent studies of normal human lymphocytes have contributed to our enormously expanding knowledge of their basic biology, especially regulatory pathways, both extracellular and intracellular. Further work with human lymphoid neoplasms has helped extend the early chromosomal findings to the specific genes involved, including several regulating apoptosis; and also contributed to the concept of clonal evolution as a basic underlying mechanism of tumorigenesis in general. This career has covered a period of remarkable growth of knowledge concerning both normal and neoplastic lymphocytes, with potential for many important future clinical applications; it has been a privilege to participate.

Tumor progression: a brief historical perspective.

It has long been known that tumors become more clinically and biologically aggressive over time. This has been termed 'tumor progression' and includes, among other properties invasion and metastasis, as well as more efficient escape from host immune regulation. Since 1960, first cytogenetics and then molecular techniques have shown that tumors expand as a clone from a single altered cell, and that clinical 'progression' is the result of sequential somatic genetic changes, generating increasingly aggressive subpopulations within the expanding clone. Multiple types of genes have been identified, and they differ in different tumors, but they provide potential specific targets for important new therapies.