Chronic myeloid leukemia and HIV-infection

The incidence of non-HIV-associated hematologic malignancies, including chronic myeloproliferative disorders, is increasing in HIV-infected (HIVþ) patients. This is thought to be due to prolonged survival in the era of highly active antiretroviral therapy (HAART). Previously, only six cases of chronic myeloid leukemia (CML) have been described in HIVþ individuals and limited information is available regarding the management of patients with concurrent CML and HIV- infection. We report three cases of CML in HIVþ patients who were treated with imatinib and HAART. Treatment was generally well tolerated, and cytogenetic response (complete in two patients) was achieved with follow-up ranging from 3 to 69 months. HIV viral load remained undetectable and CD4 cell counts were stable in all three patients. Concurrent treatment with imatinib and HAART can result in appropriate control of CML and HIV-infection as well as long-term survival

Aggressive presentation of breast implant-associated ALK-1 negative anaplastic large cell lymphoma with bilateral axillary lymph node involvement

We recently encountered a unique case of breast silicone implant-associated ALK-1 negative anaplastic large cell lymphoma (ALCL) in a female with a remote history of breast carcinoma, which presented as a sinusoidal infiltrate in an axillary lymph node (LN) and had a highly complex karyotype

Identification of rare Epstein-Barr virus infected memory B cells and plasma cells in non-monomorphic post-transplant lymphoproliferative disorders and the signature of viral signaling

Background and Objectives. In early and polymorphic post-transplant lymphoprolifera- tive disorders (PTLD) Epstein-Barr virus (EBV), through its latency proteins, drives the proliferation of B lymphocytes, a process which in immunocompetent individuals leads to the establishment of latently infected memory B cells. Design and Methods. We analyzed 11 cases, which included early and polymorphic PTLD, and 12 controls for latency of EBV infection and their antigenic profile. Results. We identified a minority of terminally differentiated EBER+ IRTA1+ memory B cells and EBER+ CD138+ PRDM1+ plasma cells in these samples. These elements were identified both in PTLD and in tumor-free tonsils from post-transplant patients but not in EBV– control tonsils. The expression of EBV latency proteins is heterogeneous, and is associated with activation of the NF-κB pathway. EBV signaling (through EBNA2, LMP1 and LMP2A) and NF-κB activation correlated with upregulation of target proteins: cMYC, JunB, CCL22, TRAF1 and IRF4. EBV-infected lymphocytes in early and polymor- phic PTLDs represent a mixture of latencies II, III and, in at least 1/3 of infected cells, of latency 0. Interpretation and conclusions. EBV infection correlates with NF-κB activation, with EBV-dependent cell signaling, and lastly, with the presence of EBV-infected plasma cells and memory cells. Key words: post-transplant lymphoproliferative disorder, Epstein-Barr virus, viral latency, NF-κB signaling, plasma cell, memory B cell

Do RARA/PML fusion gene deletions confer resistance to ATRA-based therapy in patients with acute promyelocytic leukemia?

Acute promyelocytic leukemia (APL) is characterized by the translocation t(15;17)(q22;q21), resulting in the promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) fusion protein in 95% cases whereas variant translocations involving PLZF (11q23), NPM (5q35), NUMA (11q13) and STAT5b (17q23) account for the rest. Leukemias with PML-RARA translocations respond well to all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) therapy whereas those with PLZF-RARA fusions respond poorly. Although primary resistance to ATRA is rare, secondary or acquired resistance is frequently observed in patients treated with ATRA alone or in combination with other chemotherapy regimens. However, molecular abnormalities mediating resistance to ATRA therapy are underexplored. Here, we report two cases of APL with RARA-PML deletions on der(17) or der(15), which displayed clinical evidence of primary and secondary resistance to therapy, respectively

Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b \u3csup\u3e+\u3c/sup\u3eLy6G\u3csup\u3e+\u3c/sup\u3e immature myeloid cells

Histidine decarboxylase (HDC), the unique enzyme responsible for histamine generation, is highly expressed in myeloid cells, but its function in these cells is poorly understood. Here we show that Hdc-knockout mice show a high rate of colon and skin carcinogenesis. Using Hdc-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the Hdc promoter, we show that Hdc is expressed primarily in CD11b +Ly6G+ immature myeloid cells (IMCs) that are recruited early on in chemical carcinogenesis. Transplant of Hdc-deficient bone marrow to wild-type recipients results in increased CD11b + Ly6G + cell mobilization and reproduces the cancer susceptibility phenotype of Hdc-knockout mice. In addition, Hdc-deficient IMCs promote the growth of tumor allografts, whereas mouse CT26 colon cancer cells downregulate Hdc expression through promoter hypermethylation and inhibit myeloid cell maturation. Exogenous histamine induces the differentiation of IMCs and suppresses their ability to support the growth of tumor allografts. These data indicate key roles for Hdc and histamine in myeloid cell differentiation and CD11b+Ly6G+IMCs in early cancer development. © 2011 Nature America, Inc. All rights reserved

The spectrum of myelodysplastic syndromes post-solid organ transplantation: A single institutional experience

An increased incidence of acute myeloid leukemia (AML) has recently been documented in patients post-solid organ transplantation but the incidence and types of myelodysplastic syndromes (MDS) occurring in this patient population are not known. We identified 5 patients (3M, 2F, age 48–64 years) who developed MDS ranging from 1.8 to 25 years (median 4.2 years) post-solid organ transplantation, only 2 patients had received azathioprine. The cumulative incidence of MDS in heart and lung transplant recipients at 15 years was 0.5% and 1.8%, respectively, which is markedly higher compared to the general population. Low-risk types of MDS predominated, 3 of 5 patients are alive (median 3.9 years) since diagnosis. Deletions of chromosome 20q, which have not been previously reported in post-transplant MDS/AML, were identified in 3 cases. Our findings expand the morphologic and cytogenetic spectrum of MDS occurring post-solid organ transplantation and suggest that mechanisms beside azathioprine toxicity might be important in disease pathogenesis

Interferon-γ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T cell apoptosis

Author Manuscript 2012 June 15.IFN-γ mediates responses to bacterial infection and autoimmune disease, but it is also an important tumor suppressor. It is upregulated in the gastric mucosa by chronic Helicobacter infection; however, whether it plays a positive or negative role in inflammation-associated gastric carcinogenesis is unexplored. To study this question, we generated an H[superscript +]/K[superscript +]-ATPase-IFN-γ transgenic mouse that overexpresses murine IFN-γ in the stomach mucosa. In contrast to the expected proinflammatory role during infection, we found that IFN-γ overexpression failed to induce gastritis and instead inhibited gastric carcinogenesis induced by interleukin-1beta (IL-1β) and/or Helicobacter infection. Helper T cell (Th) 1 and Th17 immune responses were inhibited by IFN-γ through Fas induction and apoptosis in CD4 T cells. IFN-γ also induced autophagy in gastric epithelial cells through increased expression of Beclin-1. Finally, in the gastric epithelium, IFN-γ also inhibited IL-1β- and Helicobacter-induced epithelial apoptosis, proliferation, and Dckl1[superscript +] cell expansion. Taken together, our results suggest that IFN-γ coordinately inhibits bacterial infection and carcinogenesis in the gastric mucosa by suppressing putative gastric progenitor cell expansion and reducing epithelial cell apoptosis via induction of an autophagic program. Cancer Res; 71(12); 4247–59

PCDH10 Promoter Hypermethylation is Frequent in most Histologic Subtypes of Mature Lymphoid Malignancies and Occurs Early in Lymphomagenesis

PCDH10 is epigenetically inactivated in multiple tumor types; however, studies in mature lymphoid malignancies are limited. Here, we have investigated the presence of promoter hypermethylation of the PCDH10 gene in a large cohort of well-characterized subsets of lymphomas. PCDH10 promoter hypermethylation was identified by methylation-specific PCR in 57 to 100% of both primary B- and T-cell lymphoma specimens and cell lines. These findings were further validated by Sequenom Mass-array analysis. Promoter hypermethylation was also identified in 28.6% cases of reactive follicular hyperpla- sia, more commonly occurring in states of immune deregulation and associated with rare presence of clonal karyotypic aberrations, suggesting that PCDH10 methylation occurs early in lymphomagenesis. PCDH10 expression was down regu- lated via promoter hypermethylation in T- and B-cell lymphoma cell lines. The transcriptional down-regulation resulting from PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases in cell lines. Both T- and B-cell lymphoma cell lines harboring methylation-mediated inactivation of PCDH10 were resistant to doxorubicin treatment, suggesting that hypermethylation of this gene might contribute to chemotherapy response

Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma

PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients