Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1).

The mechanisms of malignant cell transformation caused by the oncogenic, chimeric nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) remain only partially understood, with most of the previous studies focusing mainly on the impact of NPM/ALK on cell survival and proliferation. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells strongly express the immunosuppressive cell-surface protein CD274 (PD-L1, B7-H1), as determined on the mRNA and protein level. The CD274 expression is strictly dependent on the expression and enzymatic activity of NPM/ALK, as demonstrated by inhibition of the NPM/ALK function in ALK+TCL cells by the small molecule ALK inhibitor CEP-14083 and by documenting CD274 expression in IL-3-depleted BaF3 cells transfected with the wild-type NPM/ALK, but not the kinase-inactive NPM/ALK K210R mutant or empty vector alone. NPM/ALK induces CD274 expression by activating its key signal transmitter, transcription factor STAT3. STAT3 binds to the CD274 gene promoter in vitro and in vivo, as shown in the gel electromobility shift and chromatin immunoprecipitation assays, and is required for the PD-L1 gene expression, as demonstrated by siRNA-mediated STAT3 depletion. These findings identify an additional cell-transforming property of NPM/ALK and describe a direct link between an oncoprotein and an immunosuppressive cell-surface protein. These results also provide an additional rationale to therapeutically target NPM/ALK and STAT3 in ALK+TCL. Finally, they suggest that future immunotherapeutic protocols for this type of lymphoma may need to include the inhibition of NPM/ALK and STAT3 to achieve optimal clinical efficacy.

A phase I study of bexarotene, a retinoic X receptor agonist, in non-M3 acute myeloid leukemia.

PURPOSE: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines. We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m(2) until evidence of disease progression or unacceptable adverse events occurred. RESULTS: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m(2)), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m(2). Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to 1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome. CONCLUSIONS: The recommended dose of bexarotene for future studies is 300 mg/m(2)/d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.

Severe eosinophilia as a manifestation of acute graft-versus-host disease.

Significant peripheral eosinophilia in association with acute graft-versus-host disease (GVHD) is rare. Here we report a case of eosinophilia in a 30-year-old woman with relapsed acute myelogenous leukemia after an allogeneic bone marrow transplant who was treated with donor lymphocyte infusion (DLI). A month after the DLI, she developed a pruritic erythematous rash, hepatic enzyme elevations and eosinophilia that peaked at 23,300 cells/mm(3). A diagnosis of acute GVHD was made and the patient was treated with corticosteroids with a resolution of all of the aforementioned findings. The authors suggest that eosinophilia in a bone marrow transplantation patient should raise suspicion of GVHD.

Evidence of myeloid differentiation in non-M3 acute myeloid leukemia treated with the retinoid X receptor agonist bexarotene.

All-trans-retinoic acid has dramatically changed the treatment paradigm for acute promyelocytic leukemia, however, it has no significant activity in non-M3 acute myeloid leukemia (AML). In vitro, bexarotene, a retinoid X receptor agonist inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts from patients. We hypothesized that there may be similar activity in patients with AML. We report on two patients with relapsed or refractory non-M3 AML treated with bexarotene monotherapy. After initiating treatment, both patients showed leukemic differentiation in their peripheral blood and reduction in bone marrow blasts to less than 5%. One patient had a significant improvement in her platelet count with loss of platelet transfusion needs. Differentiation syndrome occurred in one patient and was successfully treated with steroids and discontinuation of bexarotene. These data suggest that bexarotene has clinical activity in non-M3 AML and may be able to induce myeloid differentiation in vivo.

Pediatric primary bone lymphoma-diffuse large B-cell lymphoma: morphologic and immunohistochemical characteristics of 10 cases.

Most primary bone lymphomas (PBLs) are diffuse large B-cell lymphomas (DLBCLs). Pediatric PBL-DLBCL has a favorable prognosis but remains poorly characterized. Herein, 10 such cases are detailed. They involved 11- to 20-year-old males with bone lesions that were often painful. They were diagnosed often after months to years of symptoms, suggesting an indolent disease. All were successfully treated with chemotherapy with or without radiotherapy (0.5- to 24-year followup). Biopsy revealed that the lymphomas were paratrabecular or diffuse and were medium- to large-sized with round to irregular nuclei, dispersed chromatin, indistinct to small nucleoli, and abundant cytoplasm. Other features included varying levels of necrosis, cytoplasmic retraction, and myeloid hyperplasia. All cases marked as mature B cells, and most were CD10+ (7/10). Typical centroblastic morphologic features with nucleoli were rare, multilobated nuclei were uncommon, and CD10 negativity did not predict poor prognosis, unlike in the adult PBL-DLBCL. These findings suggest that pediatric and adult PBL-DLBCLs are distinct entities.

Burkitt lymphoma of the oral cavity: an atypical presentation.

Burkitt lymphoma (BL) is an aggressive form of non-Hodgkin B-cell lymphoma with 3 variants: endemic, sporadic, and immunodeficiency-associated types. The sporadic form, most commonly involving the abdomen and ileocecal region, presents as an abdominal mass, rarely presenting in the orofacial region. A 36-year-old Indian female presented to the Hospital of the University of Pennsylvania for evaluation of a persistent intraoral swelling ulceration of the lower right mandibular alveolar ridge with minimal bony invasion. Progressive systemic symptoms of fatigue, weakness, and fever developed without resolution following treatment for a presumed odontogenic infection in the 4 weeks before presentation. An incisional biopsy revealed a diffuse proliferation of intermediate- to large-sized lymphocytes with multiple small peripheral nucleoli, scant cytoplasm, and nuclear pleomorphism. Nearly all cells displayed Ki67 expression. A final diagnosis of BL was rendered following confirmation of a cMYC translocation by fluorescence in situ hybridization. This article presents a case of the sporadic form of BL with atypical presentation clinically and morphologically, primarily involving the oral soft tissue.

The 8p11 myeloproliferative syndrome: review of literature and an illustrative case report.

The 8p11 myeloproliferative syndrome (EMS), also called stem cell leukemia/lymphoma (SCLL), is a relatively rare condition characterized in its typical form by the occurrence, either simultaneously or sequentially, of a bcr/abl-negative myeloproliferative disorder and a lymphoma, usually a precursor T lymphoblastic lymphoma. The disease most often terminates in acute myeloid leukemia which is resistant to conventional chemotherapy. The defining cytogenetic abnormality, a translocation at the 8p11 locus, always involves the fibroblast growth factor 1 (FGFR1) gene. To date, eight partner genes have been identified in association with FGFR1 rearrangements. The most frequent FGFR1 translocation partner is the zinc finger gene ZNF198 located at 13q11. The t(8;13)(p11;q11) disrupts intron 8 of the FGFR1 gene and fuses proline-rich and zinc finger domains of the ZNF198 gene with the cytoplasmic tyrosine kinase domain of FGFR1. Oligomerization of the fusion protein occurs, with subsequent activation of downstream signal transduction pathways, culminating in neoplastic cell transformation. This review describes the historical development of the EMS/SCLL and outlines its cytogenetic abnormalities and molecular mechanisms with an illustrative case.

Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication.

Deregulation of cyclin D1 occurs in numerous human cancers through mutations, alternative splicing, and gene amplification. Although cancer-derived cyclin D1 mutants are potent oncogenes in vitro and in vivo, the mechanisms whereby they contribute to neoplasia are poorly understood. We now provide evidence derived from both mouse models and human cancer-derived cells revealing that nuclear accumulation of catalytically active mutant cyclin D1/CDK4 complexes triggers DNA rereplication, resulting from Cdt1 stabilization, which in turn triggers the DNA damage checkpoint and p53-dependent apoptosis. Loss of p53 through mutations or targeted deletion results in increased genomic instability and neoplastic growth. Collectively, the data presented reveal mechanistic insights into how uncoupling of critical cell cycle regulatory events will perturb DNA replication fidelity, thereby contributing to neoplastic transformation.