Acute Leukemias - Republican Scientific Medical Library

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102 Chapter 6 · Molecular Biology and Genetics to be absent in T-cell ALL but present in B-cell ALL and AML [104]. The Smad3 transcript was intact in all leukemia subtypes. These data suggest that Smad3 is functioning as a tumor-suppressor gene in T-cell ALL. In mice, loss of one allele for Smad3 works in tandem with homozygous inactivation of p27 Kip1 to promote T-cell leukemogenesis [104]. It will be of interest to understand the mechanism leading to the downregulation of Smad3 in this disease. 6.5.4 FLT3 FLT3 activating mutations are in general rare in ALL but have been detected in approximately 20% of ALL with rearrangement of the MLL gene [38, 105, 106], 25% of hyperdiploid ALL [106, 107], and in the rare subset of CD117/KIT-positive, CD3-positive ALL [108]. Interestingly, the internal tandem duplication of the FLT3 gene, commonly detected in AML, has thus far not been seen in ALL. Flt3 inhibitors (e.g., PKC412, CEP-701) can suppress FLT3-positive ALL and therefore warrant clinical trials [105, 109]. 6.5.5 TLX1 Gene expression profiles in T-cell ALL revealed five different signature patterns: TLX1 (HOX11), TLX3 (HOX11L2), TAL1 plus LMO1/2, LYL1 plus LMO2, and MLL-ENL [110]. Only the TLX1-expressing samples were associated with a favorable outlook in children [111] and adults [112] with T-cell ALL. Interestingly, these results were not reproduced by another group [100] and therefore will require further validation prior to implementing treatment strategies according to the presence or absence of TLX1 gene expression. 6.5.6 Cryptic t(5;14)(q35;q32) and the Overexpression of the TLX3 Gene TLX3 gene expression was shown to represent one of the five signature patterns in T-cell ALL [110]. This gene is located on chromosome 5q35 and was found to be transcriptionally activated as a result of a translocation between chromosome 5 and 14, t(5;14)(q35;q32) [113]. Studying samples from 23 childhood T-cell ALL patients revealed that this translocation was cryptic in five of them [113]. Larger studies [114, 115] have confirmed the cryptic nature of this translocation. Further, in a few cases, TLX3 was overexpressed without the presence of the translocation by either conventional cytogenetic or FISH analyses, suggesting a different mechanism leading to the gene overexpression. Finally, overexpression of TLX3 was reported by one group [116] to be associated with poor prognosis but this has not been confirmed by other larger studies [114, 115]. 6.5.7 NOTCH1 NOTCH1 point mutations, insertions and deletions producing aberrant increases in NOTCH1 signaling are frequently present in T-cell ALL [117–119]. Further, NOTCH1 signaling was shown to be required for sustained growth and, in a subset of cell lines, for survival. Finally, experiments with small molecule inhibitors of csecretase, a protease required for normal NOTCH signal transduction and the activity of the mutated forms of NOTCH1, found inhibitory activity in T-cell ALL with NOTCH1 mutations. These results provide a rationale for clinical trials with NOTCH1 inhibitors, such as c-secretase antagonists [118, 119]. 6.5.8 Pharmacogenetics Pharmacogenetics is the study of genetic variations in drug-processing genes and individual responses to drugs [120]. It enables the improved identification of patients at higher risk for either disease relapse or chemotherapy-associated side effects. In pharmacogenetic studies, single nucleotide polymorphisms and rarely haplotypes, that is, larger variations across a gene, are usually analyzed. To our knowledge, these studies have been performed only in pediatric ALL and studies in adult ALL are warranted. It was recognized, more than 20 years ago, by measuring enzyme activity, that the activity of thiopurine- S-methyltransferase (TPMT), the enzyme involved in the metabolism of 6-mercaptopurine and 6-thioguanine, differs among patients and that approximately one in 300 individuals demonstrates reduced enzyme activity [121–125]. Molecular testing to identify this polymorphism was developed shortly thereafter [126, 127] and depicted good correlation with the enzymatic activity. Based on the molecular testing it has become
a References 103 clear that homozygous carriers for one of the three TPMT mutant alleles experience severe myelotoxicity and increased risk of relapse due to treatment delays [128, 129]. Interestingly, patients with the mutated TPMT alleles have a significantly higher risk of developing secondary brain tumors if treated with whole-brain radiation [130]. Similarly, there was a trend towards increased risk of secondary AML in patients with decreased enzymatic activity [131]. Similarly, single nucleotide polymorphism involving four of the enzymes involved in methotrexate metabolism have been implicated in increased relapse risk or toxicity in pediatric ALL patients: methylenetetrahydrofolate reductase [132–136], reduced folate carrier [137– 139], thymidylate synthetase [140, 141], and methylenetetrahydrofolate dehydrogenase [136]. The results of these analyses are not always statistically significant; the discrepancies may be due to different patient populations, an assortment of treatment protocols and/or small patient numbers. 6.6 Future Directions We believe that progress in cytogenetic and genetic dissection of ALL will lead to risk-adapted treatment in adult ALL as is already being accomplished for pediatric ALL. Currently, allogeneic transplantation in first remission is offered to adults with unfavorable karyotypes. The future promises a more refined approach, based on the information from genetic analyses, that will hopefully lead to improved outcome in adult ALL. References 1. Bloomfield CD, Secker-Walker LM, Goldman AI, et al. (1989) Sixyear follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia. Cancer Genet Cytogenet 40(2):171–185 2. Fenaux P, Lai JL, Morel P, et al. (1989) Cytogenetics and their prognostic value in childhood and adult acute lymphoblastic leukemia (ALL) excluding L3. Hematol Oncol 7(4):307–317 3. Walters R, Kantarjian HM, Keating MJ, et al. (1990) The importance of cytogenetic studies in adult acute lymphocytic leukemia. Am J Med 89(5):579–587 4. Hématologique GFdC (1996) Cytogenetic abnormalities in adult acute lymphoblastic leukemia: Correlations with hematologic findings outcome. A Collaborative Study of the Group Francais de Cytogenetique Hematologique. Blood 88(7):3135–3142 5. Secker-Walker LM, Prentice HG, Durrant J, Richards S, Hall E, Harrison G (1997) Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA. MRC Adult Leukaemia Working Party. Br J Haematol 96(3):601–610 6. Faderl S, Kantarjian HM, Talpaz M, Estrov Z (1998) Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 91(11):3995–4019 7. Chessells JM, Hall E, Prentice HG, Durrant J, Bailey CC, Richards SM (1998) The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA compared: A report from the MRC Paediatric and Adult Working Parties. Leukemia 12(4):463–473 8. Wetzler M, Dodge RK, Mrozek K, et al. (1999) Prospective karyotype analysis in adult acute lymphoblastic leukemia: The cancer and leukemia Group B experience. Blood 93(11):3983–3993 9. Gleissner B, Rieder H, Thiel E, et al. (2001) Prospective BCR-ABL analysis by polymerase chain reaction (RT-PCR) in adult acute B-lineage lymphoblastic leukemia: Reliability of RT-nested-PCR and comparison to cytogenetic data. Leukemia 15(12):1834– 1840 10. Block AW, Carroll AJ, Hagemeijer A, et al. (2002) Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: Report from an international workshop. Genes Chromosomes Cancer 33(4):401–412 11. Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM (1999) The biology of chronic myeloid leukemia. N Engl J Med 341(3):164–172 12. Kantarjian HM, Talpaz M, Dhingra K, et al. (1991) Significance of the P210 versus P190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia. Blood 78(9): 2411–2418 13. Westbrook CA, Hooberman AL, Spino C, et al. (1992) Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: A Cancer and Leukemia Group B Study (8762). Blood 80(12):2983–2990 14. Melo JV, Gordon DE, Tuszynski A, Dhut S, Young BD, Goldman JM (1993) Expression of the ABL-BCR fusion gene in Philadelphia-positive acute lymphoblastic leukemia. Blood 81(10): 2488–2491 15. Lim LC, Heng KK, Vellupillai M, et al. (1999) Molecular and phenotypic spectrum of de novo Philadelphia positive acute leukemia. Int J Mol Med 4(6):665–667 16. van Rhee F, Hochhaus A, Lin F, Melo JV, Goldman JM, Cross NC (1996) p190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias. Blood 87(12):5213–5217 17. Secker-Walker LM, Craig JM, Hawkins JM, Hoffbrand AV (1991) Philadelphia positive acute lymphoblastic leukemia in adults: Age distribution, BCR breakpoint and prognostic significance. Leukemia 5(3):196–199 18. Rieder H, Ludwig WD, Gassmann W, et al. (1996) Prognostic significance of additional chromosome abnormalities in adult patients with Philadelphia chromosome positive acute lymphoblastic leukaemia. Br J Haematol 95(4):678–691 19. Ko BS, Tang JL, Lee FY, et al. (2002) Additional chromosomal abnormalities and variability of BCR breakpoints in Philadelphia chromosome/BCR-ABL-positive acute lymphoblastic leukemia in Taiwan. Am J Hematol 71(4):291–299 20. Gleissner B, Gokbuget N, Bartram CR, et al. (2002) Leading prognostic relevance of the BCR-ABL translocation in adult acute Blineage lymphoblastic leukemia: A prospective study of the Ger
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E.H. Estey · S.H. Faderl · H. M.
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E. H. Estey Department of Leukemia
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VI Table of Contents 14 Philadelphi
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VIII Contributors S. H. Faderl Depa
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X Contributors D. Wartenberg Depart
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Therapy of AML Elihu Estey Contents
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a 1.2 · Standard Therapy 3 Table 1
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a 1.2 · Standard Therapy 5 Table 1
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a 1.2 · Standard Therapy 7 tween G
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a 1.2 · Standard Therapy 9 Fig. 1.
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a 1.2 · Standard Therapy 11 of tre
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a 1.2 · Standard Therapy 13 Table
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a 1.2 · Standard Therapy 15 permit
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a References 17 19. Care RS, Valk P
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a References 19 6-thioguanine in th
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Acute Myeloid Leukemia: Epidemiolog
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a 3.1 · Epidemiology 49 3.1.4 Gend
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Page 79 and 80: Molecular Biology and Genetics Meir
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Page 93 and 94: Diagnosis of Acute Lymphoblastic Le
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154 Chapter 11 · Conventional Ther
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ALL Therapy: Review of the MD Ander
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a 12.2 · The Hyper-CVAD Regimen in
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a 12.3 · Subset-Specific Approache
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Treatment of Adult ALL According to
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a 13.2 · Therapy for Younger (15-6
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a 13.3 · Therapy of Ph/BCR-ABL-Pos
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a 13.5 · Prognostic Factors 173 13
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a References 175 Only patients with
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Philadelphia Chromosome-Positive Ac
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a 14.2 · Molecular Biology of the
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a 14.3 · Treatment of Ph+ ALL 181
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a 14.4 · Hematopoietic Stem Cell T
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a References 185 2. Kurzrock R, Sht
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a References 187 56. Mori T, Manabe
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a References 189 acute lymphoblasti
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192 Chapter 15 · Burkitt’s Acute
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204 Chapter 16 · Treatment of Lymp
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216 Chapter 17 · The Role of Allog
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230 Chapter 18 · The Role of Autol
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238 Chapter 19 · Novel Therapies i
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248 Chapter 20 · Minimal Residual
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264 Chapter 21 · Central Nervous S
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276 Chapter 22 · Relapsed Acute Ly
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278 Chapter 22 · Relapsed Acute Ly
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Emergencies in Acute Lymphoblastic
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a 23.5 · Hyperleukocytosis 283 LA
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a 23.9 · Neurological Complication
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a References 287 29. Hingorani AD,
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Subject Index A aberrant methylatio
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a Subject Index 291 CREB, see enhan
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a Subject Index 293 MUD, see matche
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