Yuji Yufu

High constitutive expression of heat shock protein 90α in human acute leukemia cells

Abstract The constitutive expression of the genes for four heat shock proteins (hsps) was studied in leukemia cell lines, cells obtained from patients with acute leukemia, and normal blood cells by means of Northern-blot analysis. Western-blot analysis with hsp90 antibody showed that the leukemia cells contained larger amounts of hsp90 than the normal peripheral mononuclear cells. The expression of the hsp90α gene was enhanced in the leukemia cell lines and the acute leukemia cells from patients as compared with the normal blood cells. In contrast, the expression of the hsp90β gene could hardly be recognized in either the acute leukemia cells or the normal blood cells. An increased expression of hsp70 gene was observed in only one patient. The expression of the hsp27 gene was enhanced in one-half the patients with common acute lymphoblastic leukemia. Thus, exclusively the hsp90α gene was expressed highly in the leukemia cells, indicating its association with cellular proliferation.

Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma

Programmed cell death ligand 1 (PD-L1) is expressed on both select diffuse large B-cell lymphoma (DLBCL) tumor cells and on tumor-infiltrating nonmalignant cells. The programmed cell death 1 (PD-1)/PD-L1 pathway inhibits host antitumor responses; however, little is known about how this pathway functions in the tumor microenvironment. The aim of this study was to determine the clinicopathological impact of PD-L1(+) DLBCL. We performed PD-L1/PAX5 double immunostaining in 1253 DLBCL biopsy samples and established a new definition of PD-L1(+) DLBCL. We also defined the criteria for microenvironmental PD-L1(+) (mPD-L1(+)) DLBCL (ie, PD-L1(-) DLBCL in which PD-L1(+) nonmalignant cells are abundant in the tumor microenvironment). Of the 273 patients whose clinical information was available, quantitative analysis of PD-1(+) tumor-infiltrating lymphocytes (TILs) was performed. The prevalence rates of PD-L1(+) and mPD-L1(+) DLBCL were 11% and 15.3%, respectively. Both PD-L1(+) and mPD-L1(+) DLBCL were significantly associated with non-germinal center B-cell (GCB) type and Epstein-Barr virus positivity. The number of PD-1(+) TILs was significantly higher in GCB-type tumors and lower in mPD-L1(-) and PD-L1(+) DLBCL. Patients with PD-L1(+) DLBCL had inferior overall survival (OS) compared with that in patients with PD-L1(-) DLBCL (P = .0009). In contrast, there was no significant difference in OS between mPD-L1(+) and mPD-L1(-) DLBCL (P = .31). The expression of PD-L1 maintained prognostic value for OS in multivariate analysis (P = .0323). This is the first report describing the clinicopathological features and outcomes of PD-L1(+) DLBCL. Immunotherapy targeting the PD-1/PD-L1 pathway should be considered in this distinct DLBCL subgroup.

Parvovirus B19‐associated haemophagocytic syndrome with lymphadenopathy resembling histiocytic necrotizing lymphadenitis (Kikuchi's disease)

A 15‐year‐old girl developed a haemophagocytic syndrome caused by human parvovirus B19 (PVB19). The cervical lymph node histology, resembling that of histiocytic necrotizing lymphadenitis (HNL, Kikuchi’s disease), included several transformed lymphocytes, numerous histiocytes, and massive necrosis. We detected PVB19‐positive cells in the lymph node by immunohistochemistry. Possible autoimmune mechanisms in HNL‐like diseases triggered by PVB19 are discussed.

Successful treatment of a patient with cardiac lymphoma who presented with a complete atrioventricular block

A patient with primary cardiac lymphoma, which is very rare, generally is regarded to have a poor prognosis. We herein report a patient with cardiac lymphoma who was treated successfully by systemic chemotherapy and radiotherapy using a pacemaker to control the complete atrioventricular (A‐V) block. A 70‐year‐old man had a syncope caused by a complete A‐V block. An echocardiogram, a computed tomographic scan, and magnetic resonance imaging of his chest showed a cardiac tumor. At this time, a biopsy of the cardiac tumor disclosed malignant lymphoma (diffuse large cell type, B cell type). The patient was thus treated with systemic chemotherapy and radiotherapy and, as a result, achieved a complete remission with a disappearance of the A‐V block. Recently, several successful outcomes involving primary cardiac lymphoma have been reported because of the progress in diagnostic techniques including echocardiography, computed tomographic scanning, and magnetic resonance imaging, as well as improvement in the therapy of malignant lymphoma. Our clinical experience indicated that an early and accurate diagnosis combined with the appropriate therapy can thus help in obtaining a long survival in patients with primary cardiac lymphoma. Am. J. Hematol. 59:171–174, 1998.

Soluble fas in the serum of patients with non-Hodgkin's lymphoma : Higher concentrations in angioimmunoblastic T-cell lymphoma

The soluble form of Fas (sFas) can block apoptosis induced by the Fas ligand in vitro. A recent report demonstrated that mice injected with sFas displayed autoimmune features. Therefore, an elevated serum concentration of sFas may be associated with lymphoproliferation and autoimmune diseases. We measured the serum concentrations of sFas in 77 patients with non‐Hodgkins lymphoma (NHL) [8 angioimmunoblastic T‐cell lymphoma (AIL), 12 T‐cell NHL, 53 B‐cell NHL, and 4 natural killer‐cell NHL]. Elevated concentrations of sFas were detected only in AIL, which is frequently accompanied by autoimmune diseases (P < 0.005 compared with age‐matched controls). A possible association of sFas and autoimmune features in AIL is discussed. Am. J. Hematol. 58:334–336, 1998.

Enhanced synthesis of heat shock proteins and augmented thermotolerance after induction of differentiation in HL-60 human leukemia cells

The effects of the induction of differentiation were investigated on the expression of heat shock proteins (hsps) and thermotolerance. The synthesis of the major hsps in response to heat stress was markedly enhanced in HL‐60 human leukemia cells after differentiation. An increased amount of mRNA transcripts for hsp70 was also noted. In addition, induction of differentiation resulted in acquisition of greater resistance to heat, which may be advantageous since cells in the peripheral blood must survive many stresses.

Primary Macroglobulinemia with t(11;18)(q21;q21)

These are the first cases of primary macroglobulinemia (PMG) with t(11;18)(q21;q21) reported in the literature. The first case was a 77-year-old man with macroglobulinemia (serum IgM: 8.36 g/dL). Abnormal lymphoid cells were detected in the blood and bone marrow. Immunologic and karyotypic analyses revealed that abnormal cells were positive for surface IgM-k, CD19, and CD20, negative for CD5 and CD10, and all had a t(11;18)(q21;q21). The second case was a 57-year-old woman with macroglobulinemia (serum IgM: 12.0 g/dL). Abnormal lymphoid cells were detected in blood and marrow, and cells were positive for surface IgM-lambda, CD19, and CD20, and negative for CD5 and CD10. Plasma cells bearing cytoplasmic IgM-lambda were increased in pleural fluid. Karyotyping demonstrated t(2;11;18)(q21-23;q21;q21). Rearrangements within BCL2 and YES genes located at 18q21 were not detected. Sixteen other cases with t(11;18)(q21;q21) have been reported in marginal zone B-cell lymphoma. Therefore, our report is in agreement with the finding that part of primary macroglobulinemia is a variant of marginal zone B-cell lymphoma.

Modulation of expression of multidrug resistance gene (mdr-1) by adriamycin

The acquired resistance to various drugs in cancer is mediated by P‐glycoprotein (P‐gp) which is encoded by the mdr‐1 gene. An increased level of mdr‐1/P‐gp was demonstrated after chemotherapy administered to treat cancer in humans. To clarify the direct effect of anticancer drugs on mdr‐1/P‐gp expression, we investigated the change in transport of adriamycin (ADR), and the expression of the mdr‐1 gene and P‐gp in an ADR‐treated, multidrug‐resistant leukemic cell line (K562/ADR500). The addition of ADR induced the over‐expression of mdr‐1/P‐gp, which led to a transient decrease in the intracellular accumulation of ADR although the difference was not statistically significant. A maximal effect was observed after 4 h incubation, returning to the baseline level after further incubation for 12–24 h. The phosphorylation of P‐gp was inversely correlated with the levels of P‐gp. These observations suggest that ADR itself modulates both the expression and function of P‐gp. Determination of the optimal schedule for administering adriamycin is essential to achieving the optimal effect in treating cancer.

Polyneuropathy in acute megakaryoblastic leukemia

Peripheral neuropathy is a rare complication in leukemia. The authors report a patient with acute megakaryoblastic leukemia (AMKL) and progressive symmetric polyneuropathy. Intense infiltration of leukemic cells in a peripheral nerve was observed at autopsy. This is the first report of AMKL with peripheral nerve involvement to the knowledge of the authors.

Expression of EVI1 and the Retinoblastoma genes in acute myelogenous leukemia with t(3;13)(q26;q13-14).

The EVI1 DNA‐binding protein gene on chromosome 3q26 has been reported to be activated in some leukemia cells with alterations in 3q26. We present an acute myelogenous leukemia (AML) patient with a rare chromosomal translocation, t(3;13)(q26.2;q13–14). By reverse transcription‐ polymerase chain reaction, we detected active transcription of the EVI1 gene in the patients leukemia cells. The retinoblastoma susceptibility (Rb) gene, a tumor‐suppressor gene, is located at chromosome 13q14 and is within the other translocation breakpoint in this patient. The expression of the Rb gene product was found to be substantially decreased in the patients leukemia cells by Western blotting. Southern blot analysis, however, revealed no gross abnormalities of the Rb gene. Although it is unlikely that the Rb gene is directly involved in this translocation, the loss of the Rb gene product combined with the activation of the EVI1 gene may have led to the development of leukemia.