Adult T-Cell Leukemia-Lymphoma during Pregnancy.

Adult T-cell leukemia-lymphoma (ATL) is an uncommon highly aggressive T-cell lymphoma associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. It is rarely encountered during pregnancy and is particularly challenging to treat due to its aggressive nature and because of the lack of robust data on optimal chemotherapy. We report a case of a Jamaican immigrant diagnosed with ATL during pregnancy.

Id1 transcription inhibitor-matrix metalloproteinase 9 axis enhances invasiveness of the breakpoint cluster region/abelson tyrosine kinase-transformed leukemia cells.

Breakpoint cluster region/Abelson (BCR/ABL) tyrosine kinase enhances the ability of leukemia cells to infiltrate various organs. We show here that expression of the helix-loop-helix transcription factor Id1 is enhanced by BCR/ABL in a signal transducer and activator of transcription 5 (STAT5)-dependent manner. Enhanced expression of Id1 plays a key role in BCR/ABL-mediated cell invasion. Down-regulation of Id1 in BCR/ABL leukemia cells by the antisense cDNA significantly reduced their invasive capability through the Matrigel membrane and their ability to infiltrate hematopoietic and nonhematopoietic organs resulting in delayed leukemogenesis in mice. The Id1-promoted cell invasiveness was seemingly mediated by matrix metalloproteinase 9 (MMP9). Transactivation of MMP9 promoter in BCR/ABL cells was dependent on Id1 and abrogation of the MMP9 catalytic activity by a metalloproteinase inhibitor or blocking antibody decreased invasive capacity of leukemia cells. These data suggest that BCR/ABL-STAT5-Id1-MMP9 pathway may play a critical role in BCR/ABL-mediated leukemogenesis by enhancing invasiveness of leukemia cells.

Hypereosinophilia associated with cardiac rhabdomyosarcoma.

Hypereosinophilia, defined as an absolute eosinophil count exceeding 1,500/mm(3), is caused by a limited number of disorders. Its association with malignancy is a rare occurrence that typically denotes extensive metastasis and a poor prognosis. Several theories have been proposed to explain the hypereosinophilia associated with malignancy, focusing on the production of eosinophilopoietic cytokines by tumors. We describe a patient with hypereosinophilia associated with a cardiac rhabdomyosarcoma, review the etiologies of hypereosinophilia, and discuss the possible mechanisms.

Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) represent a life-threatening complication of standard immunosuppressive therapy. The impact of novel, rapamycin-related immunosuppressive drugs on the pathogenesis of PTLDs remains undefined. METHODS: We tested the effect of everolimus (RAD, Novartis Pharma AG, Basel, Switzerland) on human PTLD-derived cells using in vitro assays and an in vivo severe combined immunodeficiency disease mouse xenotransplant model. RESULTS: Everolimus profoundly inhibited the proliferation, cell-cycle progression, and survival of the PTLD-1 cell line established from a pulmonary PTLD. Equally profound inhibition of PTLD-1 growth was achieved in vivo at well-tolerated everolimus doses of 0.5 to 5 mg/kg per day. Five mg/kg per day of everolimus, given once per day, inhibited PTLD-1 tumor volume gain by more than 10-fold in treated mice compared with untreated mice. Because the subsequent pharmacokinetic analysis indicated rapid everolimus absorption, distribution, and clearance in mice (with a half-life of 3 to 6 hr and maximum drug blood concentration reached after 0.5 to 1 hr), treatment was changed to a twice-daily regimen. Everolimus given twice daily at 0.5 mg/kg per dose inhibited tumor-volume gain by more than 60-fold and at 0.25 mg/kg per dose by more than 10-fold. Similar everolimus doses were required to prevent graft rejection in a mouse heart allotransplantation model; the highest dose tested (1.5 mg/kg twice daily) resulted in long-term graft survival in all mice that underwent transplantation. CONCLUSIONS: Everolimus displays a potent inhibitory effect on PTLD-derived cells in vitro and in vivo in a dose range leading to prevention of allograft rejection and may prove effective in both the prevention and treatment of PTLDs in transplant patients.

Frozen sections in hematopathology.

The diagnostic complexity of lymphoproliferative disorders has increased tremendously within the last decade as evidenced by the recently published World Health Organization (WHO) classification of hematological malignancies. Diagnosis of these malignancies now often requires confirmation by ancillary studies, such as immunohistochemistry, flow cytometry, cytogenetics, and/or molecular studies. In fact, in some cases, these ancillary studies are diagnostic rather than simply confirmatory; furthermore, results from these studies may play a direct role in selecting patient therapy. Importantly, this comprehensive approach to the diagnosis of hematological disorders starts at the time of receipt of fresh tissue in the anatomic pathology laboratory. Appropriate handling and triaging of this fresh tissue, which includes recognizing grossly abnormal areas, interpreting the frozen section, and deciding to send portions of the specimen to ancillary laboratories, is pivotal to the optimal diagnosis, prognostication, and ultimate management of the patient.

Expression of SHP-1 phosphatase indicates post-germinal center cell derivation of B-cell posttransplant lymphoproliferative disorders.

SHP-1 tyrosine phosphatase acts as a negative regulator of signaling by receptors for growth factors, cytokines, and chemokines and by receptors involved in immune response. Our recent study showed that SHP-1 is tightly regulated at various stages of B-cell differentiation and is expressed in the mantle and marginal zones, interfollicular B cells, and plasma cells, whereas it is nondetectable in germinal center cells. In this study we evaluated expression of SHP-1 in vitro and in vivo in nine cell lines representing three different types of EBV+ B-cell populations closely resembling or derived from posttransplant lymphoproliferative disorders (PTLDs). Furthermore, we examined tissue samples from 58 patients with B-cell PTLDs, both EBV+ (85% of the cases analyzed) and EBV- (15%). SHP-1 protein was strongly expressed in all cell lines and PTLD cases. In addition, the PTLD cases were essentially negative for germinal center B-cell markers: none expressed CD10 and only one expressed BCL-6. More than 40% expressed a late post-germinal B-cell marker, CD138. The universal expression of SHP-1, lack of expression of CD10 and BCL-6, and frequent expression of CD138 suggest that PTLDs are derived from post-germinal center B cells regardless of the EBV cell infection status. Based on the immunophenotype, B-cell PTLDs could be divided into two broad categories corresponding to the early (CD10-/BCL-6-/SHP-1+/CD138-) and late (CD10-/BCL-6-/SHP-1+/CD138+) post-germinal center cells. By being expressed earlier, SHP-1 is a more sensitive marker of post-germinal center B cells than CD138, which is seen on the terminally differentiated immunoblasts and plasma cells.

Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis.

BCR/ABL oncogenic tyrosine kinase activates STAT5, which plays an important role in leukemogenesis. The downstream effectors of the BCR/ABL-->STAT5 pathway remain poorly defined. We show here that expression of the antiapoptotic protein A1, a member of the Bcl-2 family, and the serine/threonine kinase pim-1 are enhanced by BCR/ABL. This up-regulation requires activation of STAT5 by the signaling from SH3+SH2 domains of BCR/ABL. Enhanced expression of A1 and pim-1 played a key role in the BCR/ABL-mediated cell protection from apoptosis. In addition, pim-1 promoted proliferation of the BCR/ABL-transformed cells. Both A1 and pim-1 were required to induce interleukin 3-independent cell growth, inhibit activation of caspase 3, and stimulate cell cycle progression. Moreover, simultaneous up-regulation of both A1 and pim-1 was essential for in vitro transformation and in vivo leukemogenesis mediated by BCR/ABL. These data indicate that induction of A1 and pim-1 expression may play a critical role in the BCR/ABL-dependent transformation.