抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Background BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. Methods We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. Results Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic res...

https://www.nejm.org/doi/pdf/10.1056/NEJM200104053441401?articleTools=true

Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia

The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.

Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.

Background Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. Methods We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. Results After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 perce...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa022457

Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia

Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, we find that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined. In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI-571 resistance in a reconstitution experiment. In three patients, resistance was associated with progressive BCR-ABL gene amplification. These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI-571 resistance.

/pdf/clinical-resistance-to-sti-571-cancer-therapy-caused-by-bcr-2rxf0bytbo.pdf

Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification

The v-abl gene in Abelson virus induces pre-B-cell lymphoma in mice while the BCR/ABL oncogene is associated with chronic myelogenous leukemia and some cases of acute lymphocytic leukemia in humans. Understanding the mechanisms by which these oncogenes affect various cell types has been hampered by a paucity of experimental systems that reproduce the range of biological effects associated with them. We have developed an experimental system in which murine hematopoietic stem cell populations are infected with either v-abl or BCR/ABL retroviruses and are used to reconstitute lethally irradiated mice. Irrespective of the form of activated abl, greater than 90% of the animals reconstituted with such cells develop tumors. About 50% of them develop a myeloproliferative syndrome that shares several features with the chronic phase of chronic myelogenous leukemia; the remaining animals succumb to pre-B-cell lymphomas. The myeloproliferative syndrome is characterized by large numbers of clonally derived, infected myeloid cells. This model will allow study of the mechanism by which activated abl genes affect hematopoietic precursors in chronic myelogenous leukemia. Furthermore, our results demonstrate that introduction of an activated abl gene into the appropriate target cell, not the structure of the gene, is the major determinant in myeloid cell specificity.

Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL

The Philadelphia chromosome [t(9;22)-(q34;q11)] is the cytogenetic hallmark of human chronic myelogenous leukemia. RNA splicing joins sequences from a gene on chromosome 22 (BCR) across the translocation breakpoint to a portion of the ABL oncogene from chromosome 9, resulting in a chimeric protein (P210) that is an active tyrosine kinase. Although strongly correlated with this specific human neoplasm, and implicated as an oncogene by analogy to the gene product of the Abelson murine leukemia virus, the P210 gene had not been tested directly for oncogenic potential in hematopoietic cells. We have used a retroviral gene-transfer system to express P210 in mouse bone marrow cells. When infected bone marrow is plated under conditions for long-term culture of cells of the B-lymphoid lineage, cells expressing high amounts of P210 tyrosine kinase dominate the culture and rapidly lead to clonal outgrowths of immature lymphoid cells. Expression of P210 is growth-stimulatory but not sufficient for full oncogenic behavior. Some clonal lines progress toward a fully malignant phenotype as judged by increased cloning efficiency in agar suspension and frequency and rapidity of tumor induction in syngeneic mice. Such in vitro systems should be useful in evaluating the sequential and perhaps synergistic involvement of the P210 gene and other oncogenes as models for the progressive changes observed in human chronic myelogenous leukemia.

In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome

In the Philadelphia chromosome (Ph1) of chronic myelogenous leukemia (CML), the c-abl gene on chromosome 9 is translocated to bcr on chromosome 22. This results in the expression of a chimeric bcr-abl message that encodes the P210bcr-abl tyrosine kinase. The cells of 10% of acute lymphocytic leukemia patients (ALL) carry a cytogenetically similar Ph1 translocation. We report that Ph1-positive ALL cells express unique abl-derived tyrosine kinases of 185 and 180 kilodaltons that are distinct from the bcr-abl-derived P210 protein of CML. The appearance of the 185/180-kilodalton proteins correlates with the expression of a novel 6.5-kilobase messenger RNA. Thus, similar genetic translocations in two different leukemias result in the expression of distinct c-abl-derived products.

https://science.sciencemag.org/content/sci/235/4784/85.full.pdf

Unique forms of the abl tyrosine kinase distinguish Ph1-positive CML from Ph1-positive ALL

https://www.cell.com/cell/pdf/0092-8674(94)90240-2.pdf

The nuclear tyrosine kinase c-abl negatively regulates cell growth

To determine the functional importance of Ras in transformation by Abl oncogenes, we used a genetic approach to measure the effect of impaired Ras activity on the ability of Bcr-Abl or v-Abl to transform cells. Expression of the catalytic domain of the GTPase activating protein for Ras (Gap C terminus) impaired soft agar colony formation by fibroblasts expressing v-Abl or Bcr-Abl by 70-80%. To test Ras function in a model that more closely resembles clinical diseases involving Bcr-Abl, double gene retroviruses expressing Bcr-Abl paired with the Gap C terminus or dominant negative Ras were introduced into naive mouse bone marrow cells. Transformation by Bcr-Abl was completely blocked in both situations. Coexpression of normal c-H-Ras accelerated the transforming activity of Bcr-Abl. These findings show that Ras activation is essential for the leukemogenic activity of Abl oncogenes in two distinct model systems. The results genetically define a connection between the Bcr-Abl cytoplasmic tyrosine kinase and Ras and add to the accumulating evidence that deregulation of Ras is a central event in the genesis of a number of molecularly distinct forms of human myeloid leukemia.

/pdf/genetic-requirement-for-ras-in-the-transformation-of-55w1sk52vq.pdf

Jami McLaughlin

Papers

Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL

In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome

Unique forms of the abl tyrosine kinase distinguish Ph1-positive CML from Ph1-positive ALL

The nuclear tyrosine kinase c-abl negatively regulates cell growth

Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene.