Association of initial response to prednisone treatment in childhood acute lymphoblastic leukaemia and polymorphisms within the tumour necrosis factor and the interleukin-10 genes

Lauten, Melchior; Matthias, Thushara; Stanulla, Martin; Beger, Carmela; Welte, Karl; Schrappe, Martin

doi:10.1038/sj.leu.2402545

Cited by 63 publications

(38 citation statements)

References 47 publications

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“…In concert with other observations, such as cytokine gene polymorphisms in IFN-g 22 and IL-10 genes, 23 this finding substantiates the concept of immunosurveillance in B-precursor ALL. Dendritic cell deficiencies in pediatric ALL patients B Maecker et al…”

Section: Discussionsupporting

confidence: 71%

Dendritic cell deficiencies in pediatric acute lymphoblastic leukemia patients

et al. 2006

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Acute lymphoblastic leukemia (ALL) cells are particularly poor at generating anti-leukemia immunity, despite residing in lymphoid organs. To assess a potential role of dendritic cells (DC) in poor anti-leukemia immunity, we analyzed peripheral blood DC in 55 pediatric ALL patients at the time of initial diagnosis and 19 age-matched healthy controls. Dendritic cells were identified by their expression of HLA-DR, lack of B, T, NK, and monocyte markers, and expression of CD11c (myeloid DC(mDC)) or BDCA-2 (plasmacytoid DC(pDC)) using flow cytometry. We found that in children with B-lineage ALL, numbers of both mDC and pDC were significantly reduced (P ¼ 0.0001). In contrast, T-lineage ALL patients showed normal pDC and significantly elevated mDC (P ¼ 0.003) levels, with normal expression of HLA-DR and co-stimulatory molecules. A decrease in DC could not be explained by general impairment of myelopoiesis, as we could not demonstrate a correlation of DC numbers with granulocyte/monocyte numbers in patients with B-lineage ALL. However, aberrant expression of myeloid surface markers on leukemic blasts was frequent in patients lacking myeloid DC indicating a potential block of DC differentiation. Thus, depletion of DC in B-lineage ALL patients may contribute to poor anti-leukemia immune responses.

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Section: Discussionsupporting

confidence: 71%

Dendritic cell deficiencies in pediatric acute lymphoblastic leukemia patients

et al. 2006

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“…No statistically significant associations were found between TNF haplotype and sex, white blood cell (WBC) counts, central nervous system involvement, immunophenotype, response to chemotherapy, and event-free survival. In contrast, Lauten et al 64 analyzed the association of TNF and IL-10 polymorphisms with response to initial treatment and risk of relapse in 135 children with ALL, treated according to BFM protocols. BFM trials use clearance of peripheral blood blasts in response to an 8-day course of prednisone for treatment stratification, and have shown rapid clearance of blasts to be a powerful prognostic indicator.…”

Section: Mary V Relling Pharmd* and Stella Davies Mdmentioning

confidence: 99%

Pediatric Acute Lymphoblastic Leukemia

Carroll,

Bhojwani,

Min

et al. 2003

Hematology

130

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The outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically with current therapy resulting in an event free survival exceeding 75% for most patients. However significant challenges remain including developing better methods to predict which patients can be cured with less toxic treatment and which ones will benefit from augmented therapy. In addition, 25% of patients fail therapy and novel treatments that are focused on undermining specifically the leukemic process are needed urgently.In Section I, Dr. Carroll reviews current approaches to risk classification and proposes a system that incorporates well-established clinical parameters, genetic lesions of the blast as well as early response parameters. He then provides an overview of emerging technologies in genomics and proteomics and how they might lead to more rational, biologically based classification systems.In Section II, Drs. Mary Relling and Stella Davies describe emerging findings that relate to host features that influence outcome, the role of inherited germline variation. They highlight technical breakthroughs in assessing germline differences among patients. Polymorphisms of drug metabolizing genes have been shown to influence toxicity and the best example is the gene thiopurine methyltransferase (TPMT) a key enzyme in the metabolism of 6-mercaptopurine. Polymorphisms are associated with decreased activity that is also associated with increased toxicity. The role of polymorphisms in other genes whose products play an important role in drug metabolism as well as cytokine genes are discussed.In Sections III and IV, Drs. James Downing and Cheryl Willman review their findings using gene expression profiling to classify ALL. Both authors outline challenges in applying this methodology to analysis of clinical samples. Dr. Willman describes her laboratory's examination of infant leukemia and precursor B-ALL where unsupervised approaches have led to the identification of inherent biologic groups not predicted by conventional morphologic, immunophenotypic and cytogenetic variables. Dr. Downing describes his results from a pediatric ALL expression database using over 327 diagnostic samples, with 80% of the dataset consisting of samples from patients treated on a single institutional protocol. Seven distinct leukemia subtypes were identified representing known leukemia subtypes including: BCR-ABL, E2A-PBX1, TEL-AML1, rearrangements in the MLL gene, hyperdiploid karyotype (i.e., > 50 chromosomes), and T-ALL as well as a new leukemia subtype. A subset of genes have been identified whose expression appears to be predictive of outcome but independent verification is needed before this type of analysis can be integrated into treatment assignment.Chemotherapeutic agents kill cancer cells by activating apoptosis, or programmed cell death. In Section V, Dr. John Reed describes major apoptotic pathways and the specific role of key proteins in this response. The expression level of some of these proteins, such as BCL2, BAX, and caspase 3, h...

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“…A polymorphism in the mannose-binding-ligand sheds some light on the influence of early infections on the risk to develop ALL. 22 Lauten et al 23 tested the association of IL10-and TNFa polymorphisms with initial response to prednisone. Unlike our study, however, these findings cannot yet readily be integrated into a mechanistic model of antitumor immunity.…”

Section: Clinical Risk Parametersmentioning

confidence: 99%