Reviews in clinical and experimental hematology最新文献

A study of the growth of primate/human T cells led to mechanisms for temporary laboratory culture of these cells (discovery of interleukin-2) and also their continuous culture (by immortalization after infection with human T-cell lymphotropic virus type 1 or 2 (HTLV-1 or 2)). Cultures of lymphocytes also led us to isolate five persisting T-tropic viruses: 1. the Hall's Island strain of gibbon ape leukemia virus, 2. HTLV-1, 3. HTLV-2, 4. human immunodeficiency virus and 5. human herpes virus-6 (HHV-6). This report is a brief synopsis of the discoveries of the first human retroviruses, the HTLV.

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infects 15-20 millions individuals worldwide. This oncoretrovirus can be transmitted through 3 ways: horizontally, vertically (mother to child) and via blood transfusion. HTLV-1 causes 2 major diseases: adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-1-associated myelopathy. Tax is a 40-kDa phosphoprotein that is encoded by the pX region of the virus. Several lines of evidence have demonstrated a central role for this protein in the immortalization or transformation of the HTLV-1 infected cells. Apart from its ability to drive transcription from the viral promoter, it also deregulates the cell cycle, inhibits apoptosis, has an effect on the maintenance of the genomic stability and induces the production of several cytokines. In addition, several arguments strongly suggest the existence of host genetic factors, that could be involved in the HTLV-1 infection as well as in the development of ATLL among HTLV-1 infected individuals. ATLL can be classified into 4 major subtypes: a smoldering type, a chronic type, a lymphoma type and a leukemic type. The demonstration by Southern blot analysis of the clonal integration of an HTLV-1 provirus in the tumoral cells represents the gold-standard to define biologically ATLL. The survival rate of ATLL patients, especially those who develop the acute leukemic or lymphomas forms, is very poor, and such clonal malignant CD4 expansion remains one of the most severe lymphoproliferations.

Human herpesvirus 8 (HHV-8), also defined Kaposi's sarcoma (KS)-associated herpesvirus, was identified by Chang and colleagues in 1994 using purely molecular techniques, before any serological evidence or virus isolation in cell culture could be achieved. HHV-8 is unique among herpesviruses because its prevalence in the general population is low and because it possesses the richest weaponry of viral oncogenes and tumor-promoting factors ever described. Eleven HHV-8-specific genes are homologs of cellular genes, which were hijacked from the host during a long parallel evolution, and at least five of such genes show both in vitro and in vivo transforming ability. HHV-8 is the causative agent of KS, but it has also been associated with different hematologic malignancies, including primary effusion lymphoma (PEL), multicentric Castelman's disease (MCD), MCD-related immunoblastic/plasmablastic lymphoma and various atypical lymphoproliferative disorders. Although low-level silent infection was detected in bone marrow stromal cells from patients with multiple myeloma, a role of HHV-8 in this disease is unlikely. As seen with KS, the incidence of HHV-8-associated lymphoproliferative disorders is increased in the setting of human immunodeficiency virus infection.

Epidemiologic and molecular observations have recently suggested that hepatitis C virus (HCV) may be the causative agent of some B-cell non-Hodgkin lymphomas (B-NHL). Epidemiologic data suggest that in Italy about 5% of B-NHL are caused by HCV. Molecular data indicate a close relationship between HCV-associated B-NHL and type II mixed cryoglobulinemia. The latter disorder appears to reflect the benign monoclonal proliferation of B cells expressing a specific cross-reactive idiotype, known as WA, that may recognize an antigen of HCV, perhaps the E2 protein. Genetic abnormalities occurring during this phase of antigen-induced clonal expansion may drive the neoplastic transformation into low- or high-grade lymphoma. The recent demonstration that splenic B cell lymphomas associated with HCV-infection may regress after successful antiviral therapy confirms a role for this virus in B-cell lymphomagenesis.

Epstein-Barr virus (EBV) is a ubiquitous member of the herpesvirus family that is associated with a variety of lymphomas and lymphoproliferative diseases. It encodes a multitude of genes that drive proliferation or confer resistance to cell death. Among these are two key viral proteins which mimic the effects of the activated cellular signaling proteins. EBV-associated lymphomas include Burkitt's lymphoma; natural killer (NK)/T-cell lymphoma, lymphoma and lymphoproliferative diseases in immunocompromized populations, and Hodgkin's lymphoma. The character of the viral association differs among these entities with some consistently associated with EBV in all populations and all parts of the world, and others associated with the virus only in particular circumstances. An example of the former is nasal NK/T-cell lymphoma, while an example of the latter is Burkitt's lymphoma. The pattern of viral gene expression also varies among tumor types with different viral genes playing key roles in different tumors and conferring sensitivity to immune surveillance. Thus some of the post-transplant lymphoproliferative diseases are exquisitely sensitive to CD8 T-cell immunosurveillance, while other tumors such as Burkitt's lymphoma may be nearly impervious to such surveillance. Knowledge of the EBV association is not only important for understanding the pathogenesis of these tumors, but is increasingly important for diagnosis, monitoring and treatment.

Adolescents with acute lymphoblastic leukemia (ALL) have a higher incidence of T-cell immunophenotype, a higher incidence of Philadelphia chromosome positive ALL, a lower incidence of high hyperdiploidy and TEL-AML1 translocation, and a lower incidence of extramedullary bulk disease compared to younger patients. There appears to be little difference between 10-15 and 16-21 year old patients. Adolescents with ALL have a lower event free survival (EFS) compared to younger patients. Adolescents 16-21 years of age treated on pediatric ALL trials have a significantly better EFS than those treated on adult trials. Pediatric treatment protocols utilize more vincristine, steroid and L-asparaginase compared to adult trials. In a recently completed Children's Cancer Group trial, adolescents 16-21 years of age had a four-year EFS of 73.1%. Avascular necrosis of bone is an important complication of therapy in adolescents with ALL.

Nucleic acid-based sequence-specific therapeutic intervention offers the potential for treatment of particular cancers without side effects. RNA interference (RNAi) induced by small interfering RNA (siRNA) (19-21 bp) is a normal cellular mechanism leading to highly specific and extraordinarily efficient degradation of the corresponding mRNA. The mechanism of RNAi as well as strategies for the design and delivery of siRNA are described. The growing role of RNAi in target validation for cancer-specific genetic aberrations is discussed. We attempt an early assessment of the potential for using RNAi technologies to treat cancer directly, especially hematologic malignancies. Promising targets for specific gene silencing in hematologic oncology include oncogenic fusion proteins and oncogenes activated by point mutations. Potency and specificity of gene silencing are the major advantages of the new RNAi technology over other nucleic acid-based gene targeting approaches. Crucial questions for pharmaceutical interventions remain. Advances in the areas of delivery, systemic spreading and duration of the silencing effect are necessary before the methodology can enter clinical oncology.

The association of specific congenital syndromes with leukemia provides an opportunity to study the process of leukemogenesis on the background of known genetic alterations. The role of the intracellular DNA damage response system in suppressing leukemia is demonstrated by the congenital disorders of genomic instability. Specific collaborations between survival and differentiation pathways characterize the leukemias observed in Down, Noonan and neurofibromatosis syndromes. As these syndromes clearly reveal, childhood leukemia arises when the delicate balance between growth, development and differentiation of the fetal and early post-natal hematopoietic system is disrupted.

The use of minimal residual disease (MRD) measurement as a "surrogate" marker of molecular response to treatment, can potentially improve the evaluation of treatment response and enable estimates of the residual leukemic cell burden during clinical remission, thereby improving the selection of therapeutic strategies and, possibly, long-term clinical outcome. The most specific and sensitive methods for MRD monitoring currently available are polymerase chain reaction amplification of fusion transcripts and rearranged immunoglobulin or antigen-receptor genes, and flow cytometric detection of aberrant immunophenotypes. Several retrospective studies in childhood acute lymphoid leukemias (ALL) have used one of the different approaches for the detection of MRD. The strong association between MRD and risk of relapse was observed in children and adult patients irrespective of the methodology used. The promising results on the predictivity of MRD evaluation at the end of induction treatment has challenged the need for a new definition of remission. There is now urgent need to incorporate MRD data in clinical studies, properly designed to address treatment questions. In this context, several ongoing cooperative study groups have adopted a MRD-based risk group classification to explore whether a better tailored treatment would result in further improvement in cure rates for children with ALL.

Chimeric fusion genes derived by chromosome translocation provide stable, sensitive and clone-specific markers for tracking the origins of leukemic cells and the natural history of disease and have been particularly informative in studies with twins concordant for leukemia and in retrospective scrutiny of archived neonatal blood spots. These data have indicated that in pediatric leukemia the majority, but not all, of the chromosome translocations arise, in utero, during fetal hemopoiesis, probably as initiating events. In most cases, functionally complementary and secondary genetic events are also required. These are acquired rapidly, and possibly in utero also, in infant acute lymphoblastic leukemia (ALL) but post-natally for most childhood ALL and acute myeloblastic leukemia (AML). An important consequence of the latter is a very variable and occasionally protracted post-natal latency (1-15 years). Another important corollary is that functional chromosomal translocations and pre-leukemic clones arise at a substantially higher frequency (approximately 100x) before birth than the cumulative incidence or risk of disease. These natural histories provide an important framework for consideration of key etiological events in pediatric leukemia.