Evolutionary theory: Personal effects.
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Animals↗
Biomedical subjects
Dan Jones
Publications and source records attributed to Dan Jones.
Mature T-cell leukemias.
Mature T-cell and NK-cell leukemias are a group of relatively uncommon neoplasms derived from mature or postthymic T-cells accounting for a relatively small percentage of lymphoid malignancies. The recent availability of modern immunophenotypic and molecular tools has allowed a better distinction of these disorders from their B-cell counterparts. Similarly, identification of recurrent cytogenetic abnormalities, as well as plausible mechanisms through which these molecular events influence cellular signaling pathways, have created further insight into the pathogenesis of these disorders. Furthermore, the availability of new agents such as alemtuzumab has generated significant interest in devising specific therapeutic strategies for these malignancies. Herein, we review the clinical and pathological features of mature T-cell leukemias.
Adult↗
T cell leukemia-1 modulates TCR signal strength and IFN-gamma levels through phosphatidylinositol 3-kinase and protein kinase C pathway activation.
A signaling role for T cell leukemia-1 (TCL1) during T cell development or in premalignant T cell expansions and mature T cell tumors is unknown. In this study, TCL1 is shown to regulate the growth and survival of peripheral T cells but not precursor thymocytes. Proliferation is increased by TCL1-induced lowering of the TCR threshold for CD4(+) and CD8(+) T cell activation through both PI3K-Akt and protein kinase C-MAPK-ERK signaling pathways. This effect is submaximal as CD28 costimulation coupled to TCL1 expression additively accelerates dose-dependent T cell growth. In addition to its role in T cell proliferation, TCL1 also increases IFN-gamma levels from Th1-differentiated T cells, an effect that may provide a survival advantage during premalignant T cell expansions and in clonal T cell tumors. Combined, these data indicate a role for TCL1 control of growth and effector T cell functions, paralleling features provided by TCR-CD28 costimulation. These results also provide a more detailed mechanism for TCL1-augmented signaling and help explain the delayed occurrence of mature T cell expansions and leukemias despite tumorigenic TCL1 dysregulation that begins in early thymocytes.
Animals↗
Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate.
PURPOSE: To determine the clinical significance of molecular response and relapse among patients with chronic myelogenous leukemia (CML) treated with imatinib. EXPERIMENTAL DESIGN: We analyzed the results of quantitative PCR in 280 patients with CML in chronic phase who achieved complete cytogenetic remission with imatinib (117 after IFN-alpha failure and 163 previously untreated). Median follow-up was 31 months (range, 3-52 months). RESULTS: Median BCR-ABL/ABL ratio before the start of therapy was 39.44 (range, 0.252-170.53). A major molecular response (BCR-ABL/ABL ratio <0.05%) was achieved in 174 (62%), and transcripts became undetectable (complete molecular response) in 95 (34%). By multivariate analysis, only treatment with high-dose imatinib (P = 0.02) was associated with achievement of a major molecular response. Nine of 166 (5%) patients who achieved a major molecular response lost their cytogenetic remission, compared with 25 of 68 (37%) among those who did not achieve this response (P < 0.0001). Patients achieving a major molecular response 12 months after the start of therapy had significantly better complete cytogenetic remission duration than others. A >1-log reduction in transcript levels after 3 months of therapy predicted for an improved probability of achieving a major molecular response at 24 months. Increasing levels of BCR-ABL transcripts predicted for a loss of cytogenetic remission only among patients who did not achieve a major molecular response. CONCLUSIONS: Achieving a major molecular response, particularly within the first year of therapy, is predictive of a durable cytogenetic remission and may be the future goal of therapy in CML.
Adolescent↗
Epstein-Barr virus is associated with all histological subtypes of Hodgkin lymphoma in Vietnamese children with special emphasis on the entity of lymphocyte predominance subtype.
Early acquisition of Epstein-Barr virus (EBV) infection is prevalent in developing countries. We studied infectious mononucleosis (IM) and the subtypes of Hodgkin lymphoma (HL) with the status of EBV infection in Vietnamese children. Among the 46 cases of HL, the male-to-female ratio was 38:8, and the mean age at presentation was 6.6 years. Similar to the subtype distribution in developed countries, cases were classified as nodular sclerosis (NSHL) subtype in 56.5% (n = 26), mixed cellularity (MCHL) in 23.9% (n = 11), lymphocyte-rich classic (LRCHL) in 8.7% (n = 4), lymphocyte depletion (LDHL) subtype in 4.4% (n = 2), and nodular lymphocyte predominance (NLPHL) subtype in 6.5% (n = 3). However, in situ hybridization for EBV-encoded RNA revealed that the tumor cells were positive in 93.2% (41/44) of cases, including all 3 cases of nodular lymphocyte predominance HL. Expression of CD20 on Reed-Sternberg cells could be demonstrated in 17% (7/42) of classic HL. The high incidence of EBV in these cases of HL was correlated with an earlier mean age of presentation of primary EBV infection (ie, IM), at 5.3 years, in this patient population, compared with an average of 15 to 19 years reported in developed countries. This study demonstrates that in an area with an earlier mean age of onset of EBV infection, nearly all cases of pediatric HL, including all histological patterns, may be related to EBV infection. The association of NLPHL with EBV is unusual, and the literature is reviewed and discussed.
Adolescent↗
Primary cutaneous B-cell lymphoma.
Primary cutaneous B-cell lymphomas include extranodal marginal zone B-cell lymphoma, follicular lymphoma, large B-cell lymphoma, and, rarely, mantle cell lymphoma. Our purpose in conducting this review was to determine the clinical and behavioral characteristics of primary cutaneous B-cell lymphomas, their relationship to infectious triggers, and therapeutic response. We conducted a retrospective chart review of 23 adult patients presenting to the dermatology clinic at M. D. Anderson Cancer Center with primary cutaneous B-cell lymphoma between January 1999 and May 2003. Primary cutaneous B-cell lymphomas generally present on the head and neck, with the trunk and extremities afflicted to a lesser extent. Patients were found to have serologic evidence of prior infection with Borrelia burgdorferi (n = 10), Helicobacter pylori (n = 5), and Epstein-Barr virus (n = 6). Overall, treatment of primary cutaneous B-cell lymphoma should involve multiple modalities; however, specific treatment aimed at concurrent or suspected infection, particularly B burgdorferi, is a helpful adjunct and may achieve complete remission in a small subset of patients.
Adult↗
JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis.
JunB is a member of the Jun family of proteins that are components of the AP-1 transcription factor complex. AP-1 is involved in cell proliferation and apoptosis. Recent evidence suggests that Hodgkin and Reed-Sternberg cells overexpress JunB and that JunB facilitates constitutive CD30 expression by binding to an AP-1 site in the CD30 promoter. In this study we surveyed JunB expression in a variety of CD30+ lymphoma types including 42 cases of anaplastic large cell lymphoma, 36 classical Hodgkin lymphoma, 15 cutaneous anaplastic large cell lymphoma, and 11 CD30+ diffuse large B-cell lymphoma. In addition, seven cases of nodular lymphocyte-predominant Hodgkin lymphoma and 42 diffuse large B-cell lymphoma, known to be CD30-, were analyzed. JunB expression was assessed using tissue microarrays, immunohistochemistry and a monoclonal antibody specific for JunB. Expression of JunB was observed in 41 of 42 cases of anaplastic large cell lymphoma, including all 21 cases positive for anaplastic lymphoma kinase and 20 of 21 (95%) negative for anaplastic lymphoma kinase. JunB was also expressed in all cases of classical Hodgkin lymphoma, cutaneous anaplastic large cell lymphoma and CD30+ diffuse large B-cell lymphoma, and in lymphomatoid papulosis. By contrast, all nodular lymphocyte-predominant Hodgkin lymphomas and diffuse large B-cell lymphomas that were CD30- were also JunB-. We conclude that JunB is expressed in virtually all CD30+ lymphomas and is a potential target for experimental therapy in patients with these tumors.
Antibodies, Monoclonal↗
Expression of heat-shock protein-90 in non-Hodgkin's lymphomas.
Heat-shock protein-90 (HSP90) inhibitors are currently being used in phase I clinical trials for treating patients with a variety of neoplasms including lymphomas. Using immunohistochemical methods, we assessed for HSP90 expression in 412 cases of non-Hodgkin's lymphoma. In B-cell lymphomas, HSP90 was moderately to strongly expressed in all cases of Burkitt's lymphoma (5/5, 100%), and in subsets of follicular lymphoma (17/28, 61%), diffuse large B-cell lymphoma (27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%), small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell lymphoma (12/38, 32%) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (3/10, 30%). HSP90 was weakly expressed in six of 14 (43%) cases of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. In T-cell lymphomas, HSP90 was moderately to strongly expressed in subsets of anaplastic large-cell lymphoma (14/24, 58%; 9/12 ALK+ and 5/12 ALK-), precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified peripheral T-cell lymphoma (8/43, 23%) and angioimmunoblastic T-cell lymphoma (2/17, 12%). HSP90 was weakly expressed in seven of 58 (12%) cases of mycosis fungoides. We conclude that HSP90 is commonly expressed in a subset of many types of B- and T-cell lymphoma. These data suggest that many lymphoma types are suitable targets for modulation of HSP90 activity, and that HSP90 inhibitors are a potential investigational therapy for lymphoma patients.
Cell Line, Tumor↗
Differential expression of WT1 gene product in non-Hodgkin lymphomas.
The tumor suppressor gene wt1 (Wilms tumor 1) encodes a zinc finger transcription factor reported to be expressed in many tumors, including mesotheliomas, carcinomas, and acute leukemias. However, WT1 expression in non-Hodgkin lymphomas (NHLs) has not been studied. The authors assessed for WT1 expression in six lymphoma/leukemia cell lines using Western blot methods after subcellular fractionation. We also assessed for WT1 expression in 167 NHLs using immunohistochemical methods. The B-cell NHLs analyzed were 18 diffuse large B-cell lymphomas, 13 marginal zone B-cell lymphomas, 9 small lymphocytic lymphomas, (DLBCLs), 8 follicular lymphomas, 6 mantle cell lymphomas, 5 Burkitt lymphomas, 3 lymphoplasmacytic lymphomas, and 2 B-cell lymphoblastic lymphomas. The T-cell NHLs analyzed were 43 anaplastic large cell lymphomas (ALCLs), 26 peripheral T-cell lymphomas unspecified, 13 angioimmunoblastic T-cell lymphomas, 6 cutaneous ALCLs, 6 cases of mycosis fungoides, 5 extranodal NK/T-cell lymphomas of nasal type, and 4 T-cell lymphoblastic lymphomas. WT1 levels were higher in cytoplasmic extracts than in nuclear extracts of the Karpas 299 and SU-DHL-1 lymphoma cell lines but were higher in nuclear extracts than in the cytoplasmic extracts of the Jurkat, HH, U-937, and K562 leukemia cell lines. In NHLs, WT1 was positive in 4 of 5 (80%) Burkitt lymphomas, 9 of 12 (75%) ALK-positive ALCLs, 3 of 6 (50%) lymphoblastic lymphomas (2 of 4 T-cell, 1 of 2 B-cell), 14 of 31 (45%) ALK-negative ALCLs, 6 of 18 (33%) DLBCLs, and 1 of 6 (17%) cutaneous ALCLs. WT1 was negative in all other NHLs tested. WT1 immunoreactivity was primarily cytoplasmic in all positive NHLs except T-cell lymphoblastic lymphoma. In conclusion, WT1 protein is frequently detected in the cytoplasm of a subset of high-grade NHLs.
B-Lymphocytes↗
Acute myeloid leukaemia with FLT3 gene mutations of both internal tandem duplication and point mutation type.
FLT3 gene mutations, either internal tandem duplication or point mutation type, are common in acute myeloid leukaemia (AML). We describe 21 AML cases with both types of gene mutations, so-called dual mutations, representing approximately 1% of all cases. Most newly diagnosed AML with FLT3 dual mutations had monocytic differentiation and a normal karyotype. Over the disease course, changes in FLT3 mutation status were seen in 89% of cases, and were associated with cytogenetic changes. We conclude that FLT3 dual mutations occur rarely in AML, and appear to be related to clonal evolution.
Acute Disease↗
inv(16)(p13q22) in chronic myelogenous leukemia in blast phase: a clinicopathologic, cytogenetic, and molecular study of five cases.
Blast phase (BP) in chronic myelogenous leukemia (CML) frequently is accompanied by cytogenetic abnormalities in addition to t(9;22)(q34;q11.2). We describe 5 patients with CML in blast phase (CML-BP) in which t(9;22) and inv(16)(p13q22) were identified by conventional cytogenetics, with confirmation of BCR-ABL and CBFss-MYH11 by fluorescence in situ hybridization. The morphologic findings at the time of BP resembled de novo acute myeloid leukemia (AML) carrying inv(16)(p13q22), with abnormal eosinophils in the bone marrow and monocytosis in the peripheral blood in all cases. In 1 patient, inv(16)(p13q22) and abnormal eosinophils were detected in the bone marrow 2 months before CML-BP. The clinical course of these patients was similar to patients with CML-BP without evidence of inv(16)(p13q22). These cases illustrate that inv(16)(p13q22) is a form of cytogenetic evolution that rarely occurs in patients with CML at the time of BP. In this setting, unlike de novo AML, inv(16)(p13q22) in CML-BP is not associated with a favorable prognosis.
Adult↗
Peripheral T-cell lymphoma with a "follicular" pattern and the perifollicular sinus phenotype.
We report a case of peripheral T-cell lymphoma (PTCL) with an exclusively "follicular" pattern at one lymph node site and a diffuse pattern at a second lymph node site. Molecular studies confirmed the clonal identity of the tumor at both sites. In the lymph node showing a follicular pattern, the tumor cells appeared to infiltrate follicles where the perifollicular sinuses remained patent. The infiltrated follicles retained nonneoplastic B cells and a follicular dendritic cell network. By contrast, in the lymph node showing diffuse involvement, intranodal sinuses were no longer identifiable and there was no evidence of tumor cells infiltrating follicles. The tumor immunophenotype was influenced by the pattern: the follicular component was positive and the diffuse component was negative for bcl-6 and CD31. We suggest that the follicular growth pattern in this case of PTCL arose secondarily to tumor spread via the perifollicular sinus.
Aged↗
T-cell prolymphocytic leukemia involving extramedullary sites.
T-cell prolymphocytic leukemia (T-PLL) can involve extramedullary sites, but the diagnosis is usually established by examination of blood and bone marrow. As a result, the histologic findings at extramedullary sites are poorly documented in the literature. We describe 19 extramedullary biopsy specimens from 14 patients with T-PLL. Skin (n = 10) was the most common site biopsied. T-PLL surrounded dermal blood vessels and appendages (n = 6), diffusely replaced dermis (n = 3), or formed a subcutaneous mass (n = 1). Other extramedullary sites included liver and lymph nodes (3 each) and spleen, lung, and cecum (1 each). In liver and lymph nodes, the neoplasm predominantly involved portal tracts and paracortex, respectively. Cytologically, the T-PLL cells were round (n = 16) or Sezary cell-like (n = 3). Nucleoli were observed in a subset of cells in 8 specimens and were prominent in 3 specimens. Immunostaining for T-cell leukemia-1 (TCL-1) was positive in specimens from 9 (64%) of 14 patients. We conclude that the prolymphocytoid features of T-PLL cells can be difficult to detect in routinely stained sections of extramedullary biopsy specimens. TCL-1 expression can aid in diagnosis at extramedullary sites.
Aged↗
Morphologic, cytogenetic, and molecular abnormalities in therapy-related acute promyelocytic leukemia.
We describe 17 cases of therapy-related acute promyelocytic leukemia (tAPL). Treatment for the initial neoplasms (mostly carcinomas and non-Hodgkin lymphomas) included radiation and chemotherapy in 11 patients, radiation in 3, and chemotherapy in 3. The interval between the initial neoplasm and tAPL ranged from 17 to 166 months (median, 40 months). Morphologically, all 13 cases with available bone marrow aspirate smears showed tAPL. Dyserythropoiesis or dysmegakaryopoiesis was identified in 11 cases. In 2 cases, too few nonneoplastic cells and, in all cases, too few maturing granulocytes were present to assess for dysplasia. Conventional cytogenetics or fluorescence in situ hybridization (FISH) showed the t(15;17)(q22;q21) in all cases; 6 as a sole abnormality, 9 with additional abnormalities, and 2 assessed only by FISH. Reverse transcription-polymerase chain reaction (PCR) studies showed PML/RARa in 13 cases (8 short form, 5 long form). Mutations of the flt3 gene were detected by PCR in 5 (42%) of 12 cases. We conclude that dysplastic features, secondary cytogenetic abnormalities, and flt3 mutations are common in tAPL.
Adult↗
Acral necrotizing mycosis fungoides.
A 65-year-old male with long-standing acral "eczema" and patches of mycosis fungoides suddenly developed a transformed, necrotizing ulcerative cutaneous T-cell lymphoma manifesting as necrotic lesions of the toe and lip. The tumor had brown and/or black eschars on the surface and grew multiple opportunistic organisms. Markers CD3, Epstein-Barr virus-encoded small RNA, and T-cell receptor g gene rearrangement were positive, with CD4, 8, 30, 56, and TIA-1 negative. In spite of initial response to radiation, the patient succumbed to infection within 3 months.
Aged↗
T-cell prolymphocytic leukemia: a single-institution experience.
BACKGROUND: T-cell prolymphocytic leukemia is an uncommon, aggressive, mature T-cell leukemia characterized by proliferation of T-cell lymphocytes. The recent availability of modern immunophenotypic and molecular tools has allowed a better distinction of this disorder from its B-cell counterpart and other mature T-cell leukemias. PATIENTS AND METHODS: The clinical, pathologic, and cytogenetic features of 57 patients with T-PLL who were evaluated at the Department of Leukemia, M. D. Anderson Cancer Center (MDACC) from 1986 to 2004 were examined. RESULTS: The most common cytogenetic abnormality was inv(14)(q11;q32), which was present in 7 patients. In all 7 patients, this abnormality was associated with other chromosomal aberrations. Patients treated with alemtuzumab at MDACC had a significantly better response rate (P = 0.02) and survival rate (P = 0.002). There were no significant differences in survival based on Tcl-1 expression or different patterns of CD4 and CD8 expression. CONCLUSION: Treatment with alemtuzumab results in higher response rates and a better survival rate in patients with T-cell prolymphocytic leukemia.
Adult↗
EBV-associated B- and T-cell posttransplant lymphoproliferative disorders following primary EBV infection in a kidney transplant recipient.
Posttransplant lymphoproliferative disorders (PTLDs) usually are of B-cell lineage and associated with Epstein-Barr virus (EBV). PTLDs of T-cell lineage are much less common and infrequently associated with EBV. We report a rare case of a girl in whom B-cell and T-cell PTLDs developed following 2 EBV-negative kidney transplants. Within 2 years of the second transplantation, the originally EBV-negative patient developed both an EBV-associated clonal B-cell PTLD involving lymph nodes and an EBV-positive T-cell PTLD involving bone marrow and liver. These proliferations occurred concurrently with evidence of primary EBV infection and high plasma viral load. The patient eventually died of multiorgan failure 5 years after the initial transplant (3 years after the second transplant). To our knowledge, only 4 cases of both B-cell and T-cell PTLDs have been reported. Only 2 cases have been proven to be monoclonal and EBV-associated, as in this case, the first following kidney transplantation.
B-Lymphocytes↗
Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma.
PURPOSE: Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 microg/kg once daily for 5 days every 3 weeks, up to eight cycles. RESULTS: Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25- histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient. CONCLUSION: Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25- B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.
Adult↗