Leukemic cell

In chronic myelogenous leukemia (CML) as well as in a subset of acute lymphoblastic leukemia (ALL) Bcr-Abl, a fusion protein of c-Abl and the breakpoint cluster region (bcr), is expressed in the cytosol of leukemic cells. This fusion protein forms homo-oligomeric complexes that display elevated kinase activity and is the causative molecular abnormality in CML and certain ALL. The transforming effect of Bcr-Abl is mediated by numerous downstream signaling pathways, including protein kinase C (PKC), Ras-Raf-ERK MAPK, JAK-STAT (see below), and PI3-kinase pathways. 

Chang, C.C., Konno, S., Wu, J.M. (1991). Enhanced expression of heat shock protein and mRNA synthesis by type I interferon in human HL-60 leukemic cells. Biochem Inti. 24, 369-377. 

The expression of many of these molecules has been studied during various stages of differentiation of normal neutrophils and also of corresponding leukemic cells employing molecular biology techniques (eg, measurements of their specific mRNAs). For the majority, cDNAs have been isolated and sequenced, amino acid sequences deduced, genes have been localized to specific chromosomal locations, and exons and intron sequences have been defined. Some important proteinases of neutrophils are listed in Table 52-12. 

Amir, H. et ah. Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells, Nutr. Cancer, 33, 105, 1999. 

The initial treatment for acute leukemias is called induction. The purpose of induction is to induce a remission, a lack of identifiable leukemic cells in the bone marrow or peripheral blood with light microscopy. This definition may change as more sensitive techniques come into play. 

In both children and adults with ALL, clinical trials have identified several risk factors that correlate with outcome (Table 92-5). Prognostic features include age, WBC count, cytogenetic abnormalities, ploidy, leukemic cell immunophe-notype, and degree of initial response to therapy.7 When these factors are combined, they predict groups of patients with varying degrees of risk for treatment failure. 

CNS prophylaxis is necessary in any treatment regimen for ALL At diagnosis, the incidence of CNS disease is less than 10%, but it increases to 50% to 75% after 1 year in patients without CNS prophylaxisA The justification for CNS prohylaxis is based on two clinical findings. First, many chemotherapeutic agents do not cross the blood-brain barrier easily. Second, the CNS is a frequent sanctuary for leukemia, and undetectable leukemic cells are present in the CNS in many patients at the time of diagnosis.6... 

Relapse is the recurrence of leukemic cells at any site after remission has been achieved. Most relapses occur during treatment or within the first 2 years of its completion. The bone marrow is the most frequent site of relapse in both ALL and AML and accounts for 90% or more of relapses. Extramedullary relapse, such as the CNS and the testes, while once common, has decreased to 5% or less because of effective prophylaxis.21... 

Ali AM, Umar-Tsafe N, Mohamed SM, et al. Apopotosis induction in CEM-SS T-lymphoblastic leukemic cell line by goniothalamin. J Biochem Mol Biol Biophys 2001 5 253-261. 

Williams, A.B. and Jacobs, R.S. (1993) A marine natural product, patellamide D, reverses multidrug resistance in a human leukemic cell line. Cancer Letters, 71, 97. 

W. T., Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells, Mol. Pharmacol. 1988, 33, 454-462. 

Cotten M, Langle-Rouault F, Kirlappos H, Wagner E, Mechtler K, Zenke M, Beug H, Bimstiel ML (1990) Transferrin-polycation-mediated introduction of DNA into human leukemic cells stimulation by agents that affect the survival of transfected DNA or modulate transferrin receptor levels. Proc Natl Acad Sci USA 87 4033 4037... 

I.N. Rich, D. Worthington-White, O.A. Garden, and P. Musk, Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na+/H+ exchanger. Blood 95, 1427-1434 (2000). 

Ex vivo studies have revealed that trichothecenes can both inhibit and stimulate leukocyte function.12 For example, trichothecenes are toxic to alveolar macrophages,13 but drive differentiation of human myeloid leukemic cells.14 Dose-dependent decreases or increases in B- and T-cell mitogen responses are observable in lymphocytes from animals exposed to T-2 toxin, DON, or various macrocyclic trichothecenes these toxins similarly impair or enhance mitogen-induced lymphocyte proliferation in vitro.12 Rank order of inhibitor potency in rodent and human lymphocyte proliferation assays is Type D > Type A group > Type B group and is dependent on degree of acylation as well as of uptake and metabolism. 

Samara, A. et al. Induction of differentiation in human myeloid leukemic cells by T-2 toxin and other trichothecenes. Toxicol. Appl. Pharmacol. 89, 418, 1987. 

Wadleigh RW, Yu SJ (1988) Detoxification of iso thiocyanate allelochemicals by glutathione transferase in three lepidopterous species. J Chem Ecol 14 1279-1288 Werck-Reichhart D, Feyereisen R (2000) Cytochromes P450 a success story. Genome Biol 1 1-9 Williams AB, Jacobs RS (1993) A marine natural product, patellamide D, reverses multidrug resistance in a human leukemic cell line. Cancer Lett 71 97-102 Yazaki K (2006) ABC transporters involved in the transport of plant secondary metabolites. FEBS Lett 580 1183-1191... 

Acridinium ester—labeled chemiluminescent probes have been utilized to detect the specific protein-coding transcripts and to distinguish between transcripts that code for the 190-kDa protein and the two closely related 210-kDa proteins. The assay is called the hybridization protection assay (D3). In this assay, RNA isolated from the patient s white blood cells is first amplified by PCR. The amplified product is incubated with the chemiluminescent probe. The unhybridized probe is removed by selective hydrolysis in sodium tetraborate buffer, containing surfactant Triton X-100 at pH 8.5, in an incubation step at 60°C for 6 min. After the sample is cooled to room temperature, the chemiluminescence of the hybridized probe is measured in a luminometer. The procedure is reported to detect one leukemic cell in a population of a million or more normal cells. It is also rapid, requiring less than 30 min. Its reliability has been attested to by correlation with results obtained on karyotypic and Southern blot analysis (D3). 

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