metallothionein and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

The development of risk-adapted therapy has improved the treatment results of acute lymphoblastic leukemia (ALL) especially in children. However, more accurate risk classifiers are warranted. In this study we aimed at defining a prognostic classifier based on DNA copy number alterations of adolescent and young adult (AYA) (10-25 yrs) ALL patients (n=60) determined by microarray CGH and the relapse status of the patients. As a result of prognostic model identification procedure, we got a model of four genes: BAK1, CDKN2C, GSTM1, and MT1F, the copy number profile combinations of which differentiated AYA ALL patients at diagnosis depending on their risk of relapse. The performance of the model was poorer on other age groups. We suggest that this kind of approach produces models simple and accurate enough for potential use in ALL routine classification.

Topics: Adolescent; Adult; bcl-2 Homologous Antagonist-Killer Protein; Child; Classification; Comparative Genomic Hybridization; Cyclin-Dependent Kinase Inhibitor p18; Gene Dosage; Glutathione Transferase; Humans; Metallothionein; Oligonucleotide Array Sequence Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Risk Assessment; Young Adult

The increased morbidity of childhood leukemia in Fallon, Nevada and Sierra Vista, Arizona has prompted great health concern. The main characteristic that these two towns share is the environmental pollution attributed to metal ore from abandoned mining operations. Consequently, we have investigated the transcriptome effects of metal ores from these endemic areas using a human T-cell acute lymphoblastic leukemia cell line (T-ALL). Metal ore from Fallon significantly increased cell growth after 24, 48 and 72 h of incubation at 1.5 microg/mL concentration, as measured by trypan-blue. Sierra Vista ore significantly increased cell growth with 0.15 and 1.5 microg/mL following 72 h of incubation. From human cDNA microarray, results indicate that in total, eight genes, mostly metallothionein (MT) genes, were up-regulated and 10 genes were down-regulated following treatment of the T-ALL cells with 0.15 and 1.5 microg/mL of metal ores at 72 h, in comparison with untreated cells. Twenty-eight metals of both ores were quantified and their presence may be associated with the cell growth rate and dose-dependent activation of transcriptomes in immature T-cells.

Topics: Arizona; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Down-Regulation; Environmental Pollution; Gene Expression; Humans; In Vitro Techniques; Metallothionein; Metals, Heavy; Mining; Nevada; Oligonucleotide Array Sequence Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA; T-Lymphocytes; Tungsten; Up-Regulation

In this investigation, untreated non-B-type acute lymphoblastic leukemia (ALL) of 104 children was analyzed using immunocytochemistry for expression of protein kinase C, proto-oncogene products (Fos, Jun, Ras) and resistance-related proteins (topoisomerase II, P-glycoprotein, glutathione S-transferase-pi, metallothionein, dihydrofolate-reductase, thymidylate-synthase). The aim of the analysis was to find out whether combining those factors with the most important clinical prognostic factor (blast cell count) can improve the prognostic value (relapse-free interval). Univariate analysis shows that protein kinase D (PKC), Fos, P-glycoprotein (P-170) and glutathione S-transferase-pi (GST-pi) are significant prognostic factors independent of blast cell count (PBC) for the relapse-free intervals of children with ALL. The presence of the proteins Fos, PKC, P-170 and GST-pi was not independent within the patient population. The multivariate analysis showed that in combination with PBC and PKC, both P-170 and GST-pi have only limited prognostic influence. Combining the factors PKC, Fos and GST-pi as a categorical variable showed that this variable is a strong prognostic factor in addition to PBC.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Child, Preschool; DNA Topoisomerases, Type II; Drug Resistance; Female; Glutathione Transferase; Humans; Immunohistochemistry; Infant; Infant, Newborn; Male; Metallothionein; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Protein Kinase C; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; ras Proteins; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase

The multidrug resistance phenomenon can be observed in cases which do not express the P170 protein and these cases are suspected as having activated different resistance phenomena. Four phenomena were studied at the time of diagnosis in a series of 35 lymphoblastic and 25 myeloblastic acute (de novo) leukemias, by an immunocytochemical method. Two energetic drug transport processes were investigated: the classical MDR/P170 and the P110/LRP56 proteins, and two physiological detoxifying activities such as the glutathione transferases (GST alpha, mu, pi) and the metallothioneins (Mts). The results demonstrate that these phenomena are independent but their synergic activity can increase their impact on the outcome. P110/LRP56 positive cases demonstrated 48.8% complete remission (CR) rate compared to 71.4% for negative tests. When P170 and P110 were both positive or negative, the CR rates were 27.3% and 81.8% respectively (p = 0.0120), and survival curves were also different (p = 0.030). The CR rate in AML or ALL is weakly affected by GST pi, alpha or mu but relapses are more frequently observed for Positive-GST pi ALL (p = 0.0658). Patients with both P170 and GST pi positive reactions had a 53.3% CR rate compared to 78.9% for both negative reactions. Survival curves for these two groups were different. The CR rate in AMl was 100% for Mts positive and 43.7% for negative cases (p = 0.050), however the median survival was totally different for these two groups (p = 0.046). CR rates were 26.6% for patients who were P170 positive and Mts negative compared to 100% for P170 negative and Mts positive (p = 0.038) patients. Survival curves were also different (p = 0.0510). We conclude that these four mechanisms induce an independent drug resistance but their synergic action increase their impact on the outcome. The metallothioneins seem to have a major impact on the drug resistance phenomenon and its effect should be investigated with high priority, in the light of these results.

Topics: Adolescent; Adult; Aged; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Child, Preschool; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Glutathione Transferase; Humans; Infant; Isoenzymes; Leukemia, Myeloid, Acute; Male; Metallothionein; Middle Aged; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vault Ribonucleoprotein Particles

DNA constructs encoding BCR/ABL P210 have been introduced into the mouse germ line using microinjection of one-cell fertilized eggs. Kinetics of BCR/ABL P210 expression in transgenic mice were very similar to those of BCR/ABL P190 constructs in transgenic mice. mRNA transcripts were detectable early in embryonic development and also in hematopoietic tissue of adult animals. Expression of BCR/ABL in peripheral blood preceded development of overt disease. P210 founder and progeny transgenic animals, when becoming ill, developed leukemia of B, T-lymphoid, or myeloid origin after a relatively long latency period. In contrast, P190-transgenic mice exclusively developed leukemia of B-cell origin, with a relatively short period of latency. The observed dissimilarities are most likely due to intrinsically different properties of the P190 and P210 oncoproteins and may also involve sequences that control transgene expression. The delayed progression of BCR/ABL P210-associated disease in the transgenic mice is consistent with the apparent indolence of human chronic myeloid leukemia during the chronic phase. We conclude that, in transgenic models, comparable expression of BCR/ABL P210 and BCR/ABL P190 results in clinically distinct conditions.

Topics: Animals; B-Lymphocytes; Base Sequence; Blast Crisis; Disease Models, Animal; Embryonal Carcinoma Stem Cells; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; Humans; Leukemia, Experimental; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Metallothionein; Mice; Mice, Transgenic; Molecular Sequence Data; Molecular Weight; Neoplastic Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Recombinant Fusion Proteins; RNA, Messenger; RNA, Neoplasm; T-Lymphocytes; Transgenes

In a retrospective study we analyzed the expression of metallothionein (MT) in initial acute lymphoblastic leukemia (ALL) of 92 children and in relapsed ALL of 27 children using immunohistochemistry. MT expression was detectable in 33% of the patients with initial ALL and in 33% of the patients with relapsed ALL. No differences were seen concerning the intensity and the proportion of positively stained cells between initial and relapsed patients. The expression of MT was independent of clinical prognostic factors such as age, sex, immunological subtype, and initial blast cell count. Patients with initial ALL and MT expression tended to have a lower probability of disease-free survival compared with the MT-negative group. The relapsed patients with MT expression showed also a trend toward a shorter survival in comparison to the MT-negative group. However, the differences were not statistically significant. Thus, the results show that MT expression is not an important prognostic factor in the clinical drug resistance of childhood All.

Topics: Child; Drug Resistance; Female; Humans; Immunohistochemistry; Male; Metallothionein; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Retrospective Studies