Acute Leukemias - Republican Scientific Medical Library

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126 Chapter 8 · Diagnosis of <strong>Acute</strong> Lymphoblastic Leukemia pression of the fusion protein E2A-HLF. The E2A-PBX1 and E2A-HLF fusion proteins are strong transcription factors that appear to activate several downstream genes [23, 32, 51, 76]; both are associated with poor outcomes. 8.5.8 5q35 Abnormalities A recently described cryptic translocation in T-cell ALL, t(5;14)(q35;q32), moves the HOX11L2 (HOX11like2)(RNX; TLX3) homeobox gene into close proximity of the CTIP2 gene on chromosome 14. This translocation, which can be detected with FISH or RT-PCR, leads to overexpression of HOX11L2. Translocation t(5;14) appears to be restricted to T-lineage ALL and is more common in children than adults (22% vs. 13%) [6, 19]. 8.5.9 1p32 Abnormalities The TAL-1 (SCL; TCL-5) gene, located on chromosome 1p32, codes for a 42-kd nuclear protein with a helixloop-helix DNA binding motif. Found in approximately 25% of cases [3, 41, 63], TAL-1 alterations are the most common genetic abnormalities in T-cell ALL and can be formed by translocation or deletion. The t(1;14)(p32;q11) translocation associates TAL-1 with the T-cell receptor alpha/delta locus, whereas nonrandom, submicroscopic interstitial deletions between SIL and the 5' untranslated region of the TAL-1 gene give rise to a SIL-TAL-1 fusion transcript. Both alterations disrupt the coding potential of TAL-1 in a similar manner, leading to its ectopic expression in T cells. 8.5.10 10q24 Abnormalities Translocations involving the HOX11 homeobox gene, located on chromosome 10q24, are present in about 5% of T-cell ALL cases. Translocation t(10;14)(q24;q11) places HOX11 under transcriptional control of the T-cell receptor alpha/delta gene, while translocation t(7;10)(q35;q24) places it under control of the T-cell receptor beta gene. Both translocations lead to transcriptional activation of HOX11 (TLX1; TCL3) [30, 46, 70]. HOX11 overexpression appears to be a favorable prognostic factor in adult Tcell ALL [30]. 8.5.11 6q Abnormalities Chromosomal bands 6q15 to 6q23 are frequently deleted in T- and B-cell ALL. Such deletions have been reported in approximately 5% of cases, but are believed to be more frequently detected if PCR analysis of LOH is used. Translocations involving this region of chromosome 6, including t(6;12)(q23;p13) (ETV-6 gene) and t(6;11)(q27;q23) (a region close to the MLL gene), have also been reported. There is a suggestion that this abnormality is associated with more aggressive disease [17, 38, 54, 74]. 8.5.12 9q32 Abnormalities The TAL-2 gene encodes a helix-loop-helix protein, a transcriptional factor that activates various genes and leads to cellular proliferation [84]. The TAL-2 gene is activated by translocation t(7;9)(q34;q32), which juxtaposes it with regulatory elements of the T-cell receptor beta gene. This abnormality is rare and best detected by cytogenetic and FISH studies, but its clinical relevance has not been established. 8.5.13 T-Cell Antigen Receptor Gene Abnormalities The genes for T-cell receptors alpha/delta, gamma, and beta are located on chromosomes 14q11, 7q15, and 7q35, respectively; the delta receptor gene is located within the alpha gene. All of these loci are involved in chromosomal translocations that lead to activation of transcription factors or oncogenes [65]. The clinical relevance of the translocations that they are involved with is dependent on their partner gene. In most of these translocations the partner genes are deregulated and become under the influence of the promoter/enhancer of the T-cell receptors in a fashion similar to that seen in Burkitt leukemia. 8.5.14 13q14 Abnormalities Deletion of band 13q14 is detected in ALL and many other leukemias and tumors, suggesting the presence of tumor suppressor genes in this region. Numerous genes have been investigated as targets for this deletion,
a References 127 including the retinoblastoma gene, but none of the potential targets investigated so far have been consistently implicated. Micro-RNAs are short (21- or 22-nucleotide) RNAs transcribed from a family of closely related noncoding genes. Although their function is not completely understood, micro-RNAs are thought to regulate expression by binding mRNA of specific genes [15, 16, 50]. Two micro-RNA genes, miR15 and miR16, were recently reported to be the target for the 13q14 deletion in chronic lymphocytic leukemia and are most likely deleted in ALL. Cytogenetic and FISH studies can detect this abnormality, but higher percentage of this abnormality has been reported when LOH is used [22]. 8.5.15 9p21 Abnormalities Abnormalities of the short arm of chromosome 9 at band p21 occur in up to 15% of patients with ALL. These patients, mainly children, tend to present with unfavorable clinical characteristics (high white blood cell and blast counts and organomegaly) and predominantly Tcell immunophenotype. Clinical outcome is characterized by high relapse rates and short overall survival. The tumor suppressor genes p16 INK4a and p15 INK4b are located in this region and their products are of the cyclin-dependent kinase inhibitor (CDKI) family. Deletions of p16 INK4a and p15 INK4b are most common in T-cell ALL, where they can be found in 60–80% of cases. Hypermethylation of the 5'-CpG promoter islands silences this gene locus [28, 60, 66]. 8.5.16 Molecular Abnormalities Detected by Expression Microarrays Expression microarrays with cDNA or oligonucleotide sequences from a few to more than 33000 genes have been used to subclassify ALL and to stratify patients according to their risk and response to therapy. The expression microarray approach has yielded useful and interesting insights into the biology of ALL. It has proved useful as a discovery tool, and the data generated from this approach show that the number of genes required for specific diagnoses and subclassifications is small and can be adapted using standard diagnostic techniques such as real-time RT-PCR [8, 29, 48, 57, 68]. However, numerous technical issues related to the reproducibility and the practicality of this approach need to be resolved before it is accepted for clinical use. References 1. Aboul-Nasr R, Estey EH, Kantarjian HM, Freireich EJ, Andreeff M, Johnson BJ, Albitar M (1999) Comparison of touch imprints with aspirate smears for evaluating bone marrow specimens. Am J Clin Pathol 111:753–758 2. Armitage JO, Abedi M, Albitar M, Banks PM, Chadburn A, Chang KL, Coiffier B, Cortes JE, Deitcher SR, Dunphy CH (2004) Atlas of Clinical Hematology. Lippincott Williams & Wilkins, Hagerstown, Maryland 3. Bash RO, Hall S, Timmons CF, Crist WM, Amylon M, Smith RG, Baer R (1995) Does activation of the TAL1 gene occur in a majority of patients with T-cell acute lymphoblastic leukemia? A pediatric oncology group study. Blood 86:666–676 4. Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A, van’t Veer MB (1995) Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of <strong>Leukemias</strong> (EGIL). Leukemia 9:1783–1786 5. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1981) The morphological classification of acute lymphoblastic leukaemia: Concordance among observers and clinical correlations. Br J Haematol 47:553–561 6. Berger R, Dastugue N, Busson M, Van Den Akker J, Perot C, Ballerini P, Hagemeijer A, Michaux L, Charrin C, Pages MP, et al.; Groupe Francais de Cytogenetique Hematologique (GFCH) (2003) t(5;14)/ HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Francais de Cytogenetique Hematologique (GFCH). Leukemia 17:1851–1857 7. Bernasconi C, Brusamolino E, Pagnucco G, Bernasconi P, Orlandi E, Lazzarino M (1991) Burkitt’s lymphoma/leukemia: A clinicopathologic study of 24 adult patients. Leukemia 5(Suppl 1):90–94 8. Bertrand FE, Spengeman JD, Shah N, LeBien TW (2003) B-cell development in the presence of the MLL/AF4 oncoprotein proceeds in the absence of HOX A7 and HOX A9 expression. Leukemia 17:2454–2459 9. Blatt J, Proujansky R, Horn M, Phebus C, Longworth D, Penchansky L (1992) Idiopathic hypereosinophilic syndrome terminating in acute lymphoblastic leukemia. Pediatr Hematol Oncol 9:151–155 10. Bloomfield CD, Lindquist LL, Arthur D, McKenna RW, LeBien TW, Nesbit ME, Peterson BA (1981) Chromosomal abnormalities in acute lymphoblastic leukemia. Cancer Res 41:4838–4843 11. Braziel RM, Arber DA, Slovak ML, Gulley ML, Spier C, Kjeldsberg C, Unger J, Miller TP, Tubbs R, Leith C, et al. (2001) The Burkitt-like lymphomas: A Southwest Oncology Group study delineating phenotypic, genotypic, and clinical features. Blood 97:3713–3720 12. Brito-Babapulle V, Crawford A, Khokhar T, Laffan M, Matutes E, Fairhead S, Catovsky D (1991) Translocations t(14;18) and t(8;14) with rearranged bcl-2 and c-myc in a case presenting as B-ALL (L3). Leukemia 5:83–87 13. Brodeur GM, Williams DL, Look AT, Bowman WP, Kalwinsky DK (1981) Near-haploid acute lymphoblastic leukemia: A unique subgroup with a poor prognosis? Blood 58:14–19 14. Brunning RD (2003) Classification of acute leukemias. Semin Diagn Pathol 20:142–153
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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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a 3.2 · Etiology 51 part of the in
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a 3.2 · Etiology 53 for the develo
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a References 55 38. Crane MM, Stom
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Relapsed and Refractory Acute Myelo
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a 4.2 · Prognostic Factors in Pati
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a 4.3 · Treatment of Relapsed and
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a 4.4 · Hematopoietic Stem Cell Tr
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Page 79 and 80: Molecular Biology and Genetics Meir
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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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