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Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children. We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics. Our classifier predicted ALL subtype with a median accuracy of 90·0% (IQR 88·3–91·7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87·9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR–ABL1-positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR–ABL1-like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59·5%, 95% CI 37·1–81·9) compared with patients with other precursor B-ALL (84·4%, 76·8–92·1%; p=0·012), a prognosis similar to that of patients with BCR–ABL1-positive ALL (51·9%, 23·1–80·6%). In the DCOG cohort, the prognosis of BCR–ABL1-like disease (57·1%, 31·2–83·1%) was worse than that of other precursor B-ALL (79·2%, 70·2–88·3%; p=0.026), and similar to that of BCR–ABL1-positive ALL (32·5%, 2·3–62·7%). 36 (82%) of the patients with BCR–ABL1-like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0·0002). Compared with other precursor B-ALL cells, BCR–ABL1-like cells were 73 times more resistant to L-asparaginase (p=0·001) and 1·6 times more resistant to daunorubicin (p=0·017), but toxicity of prednisolone and vincristine did not differ. New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute, and American Lebanese Syrian Associated Charities.

Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This lack of knowledge is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX. We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial \"up-front\" in vivo MTX treatment (1 g/m(2)) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1-18 y). We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of children with ALL. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p < 0.001, p = 0.02). Together, these data provide new insights into the genomic basis of MTX resistance and interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL. Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov (NCT00137111); Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D); Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D).

Germline polymorphisms and gene-expression profiles in acute lymphoblastic leukaemia (ALL) cells are emerging as useful clinical diagnostics for this disease. Lessons learnt from development of polygenic models for ALL might inform the optimization of treatment for other cancers. Key Points Germline polymorphisms are known to influence the pharmacokinetics and pharmacological effects of a growing number of anticancer agents. Polymorphisms in the human thiopurine methyltransferase ( TPMT ) gene lead to loss of the functional protein and predispose with high penetrance to severe haematopoietic toxicity in TPMT-deficient patients, unless their dose of mercaptopurine is reduced by 90–95%. Candidate-gene strategies have shown that germline polymorphisms in additional genes — such as the glutathione S -transferase genes, the uridine-5′-diphosphate-glucuronosyl-transferase genes and the thymidylate synthetase gene — are associated with the efficacy or toxicity of chemotherapy for acute lymphoblastic leukaemia (ALL). Recently, distinct gene-expression profiles of primary ALL cells have been linked to the sensitivity of leukaemia cells to several antileukaemic agents in vitro , and these expression signatures also predicted treatment outcome. These findings provide momentum for future genome-wide studies to identify additional genomic determinants of ALL- treatment responses. These will allow the development of polygenic models that can be used to optimize the treatment of ALL and other human cancers. The use of combination chemotherapy to cure acute lymphoblastic leukaemia (ALL) in children emerged in the 1980s as a paradigm for curing any disseminated cancer, and many of the therapeutic principles were subsequently applied to the treatment of other disseminated human cancers. Similarly, elucidation of the pharmacogenomics of ALL and its translation into new chemotherapeutic approaches might serve as a model for optimizing the treatment of other human cancers. Germline polymorphisms and gene-expression patterns in ALL cells have been linked to the toxicity and efficacy of chemotherapy for ALL and are beginning to emerge as useful clinical diagnostics.

In a study of leukemia cells that were resistant or sensitive to prednisolone, vincristine, asparaginase, or daunorubicin — four drugs used in the treatment of childhood acute lymphoblastic leukemia — 124 genes were linked to resistance or sensitivity. The pattern of expression of resistance genes was independently related to the outcome of treatment. The pattern of expression was independently related to the outcome of treatment. This work adds a new dimension to the formulation of a prognosis. Improvements in the treatment of childhood acute lymphoblastic leukemia (ALL) over the past four decades have resulted in rates of long-term disease-free survival of approximately 80 percent. 1 , 2 We have shown that children whose ALL cells exhibit in vitro resistance to antileukemic agents have a substantially worse prognosis than children whose ALL cells are drug-sensitive. 3 – 5 However, little is known about the genetic basis of resistance to chemotherapy. Multidrug-resistance genes 6 and genes involved in cell-cycle progression, 7 , 8 DNA repair, 9 drug metabolism, 9 – 11 and apoptosis 12 have been associated with the prognosis of ALL, but their role in determining the sensitivity of . . .

Acute myeloid leukemia (AML) encompasses heterogeneous entities with dismal outcomes. Intermediate and unfavorable-risk AML represent the most difficult-to-treat entities. We recently reported the benefit of the clofarabine-based consolidation (CLARA) regimen compared to the standard high-dose cytarabine (HDAC) regimen in younger AML patients. Here, we aimed at assessing the clinical significance of single-nucleotide polymorphism (SNP)-array alterations and their interactions with chemotherapy regimens. A SNP-array was successfully performed in 187 out of the 221 intent-to-treat patients (CLARA arm: n = 92 patients, HDAC arm: n = 95 patients). The CLARA regimen did not significantly improve relapse-free survival (RFS) among patients who displayed a complex karyotype when compared to the HDAC regimen (4-year RFS (4y-RFS): 36.4% vs. 18.8%, respectively; p = 0.134). Defining micro-complex karyotypes from at least four SNP-array lesions enabled us to refine and enlarge the subset of adverse patients. In such patients, the CLARA regimen significantly improved RFS compared to the HDAC regimen (4y-RFS: 44.4% vs. 13.8%, respectively; p = 0.004). From our study cohort, 8% of patients displayed TP53 mutations, which were associated with an impaired RFS (4y-RFS: 20.0% vs 43.7%; p = 0.029). In a multivariate analysis, micro-complex karyotypes remained the sole poor prognostic factor in the HDAC arm (hazard ratio (HR) = 2.324 (95% confidence interval (CI) = 1.337–4.041), p = 0.003). The SNP array represents a powerful and reproductive approach to refine adverse AML patients that may benefit from alternative consolidation regimens.

To elucidate the genomics of cellular responses to cancer treatment, we analyzed the expression of over 9,600 human genes in acute lymphoblastic leukemia cells before and after in vivo treatment with methotrexate and mercaptopurine given alone or in combination. Based on changes in gene expression, we identified 124 genes that accurately discriminated among the four treatments. Discriminating genes included those involved in apoptosis, mismatch repair, cell cycle control and stress response. Only 14% of genes that changed when these medications were given as single agents also changed when they were given together. These data indicate that lymphoid leukemia cells of different molecular subtypes share common pathways of genomic response to the same treatment, that changes in gene expression are treatment-specific and that gene expression can illuminate differences in cellular response to drug combinations versus single agents.

The use of combination chemotherapy to cure acute lymphoblastic leukemia in children and acute myeloid leukemia in adults emerged for acute myeloid leukemia in the 1960s and for acute lymphoblastic leukemia in the 1980s as a paradigm for curing any disseminated cancer. This article summarizes recent developments and considerations in the use of acute leukemia xenografts established in immunodeficient mice to elucidate the genetic and genomic basis of acute leukemia pathogenesis and treatment response.

Acute myeloid leukemia (AML) in adults is a heterogeneous malignant pathology with a globally unfavorable prognosis. The classification of AML allows identification of subgroups with favorable prognosis. However, besides these specific subgroups, most patients will have an intermediate or unfavorable prognosis often resulting in induction failure, probably due to drug resistance of the leukemic blasts, and more frequently resulting in early relapse after achieving complete remission. This unfavorable situation leads to a strong need to develop new diagnostic and therapeutic options. However, development of these therapies and their efficient use requires a better understanding of the biology and the molecular pathogenesis of AML. Pharmacogenomics focuses on the genetic variation of drug-metabolizing enzymes, targets and transporters, and how these genetic variations interact to produce specific drug-related phenotypes. Potential genetic markers may serve to functionally subclassify patients by their disease and therefore influence the nature and intensity of treatment. This review summarizes important aspects of and recent advances in the field of pharmacogenomics in AML.