Acute Leukemias - Republican Scientific Medical Library

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124 Chapter 8 · Diagnosis of <strong>Acute</strong> Lymphoblastic Leukemia Table 8.1. Molecular abnormalities of acute lymphoblastic leukemia (ALL) Chromosomal abnormality 8.5.1 Hyperdiploidy Gene Cytogenetic lesion % Adult ALL % Pediatric ALL 8q24 Myc-Ig t(8;14), t(8;22), t(2,8) 5 2 >46 chromosomes NA Hyperdiploidy 5 25
a 8.5 · Cytogenetic and Molecular Abnormalities 125 of the Philadelphia chromosome is associated with uniformly poor outcomes [21, 26, 34]. Philadelphia chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11)], which moves the ABL gene from 9q34 into the BCR (breakpoint cluster region) region of chromosome 22q11. The resulting BCR-ABL fusion gene encodes a tyrosine phosphokinase that is constitutively active and leads to downstream activation of several proteins, including the Crkl and AKT pathway, Ras/Raf-1 pathway, Stat 1 and 5 pathways, plateletderived growth factor (PDGF), and the c-kit receptor tyrosine kinase [26, 34, 65]. Depending on the exact position of the translocated ABL gene (exon b2) within BCR, three different fusion products can be generated: p190 (molecular weight 190 kd, exon e1), p210 (exon b2 or b3), and p230 (exon e19). Patients with CML express mostly the p210 protein and rarely p230, whereas ALL patients mainly express p190. Some ALL patients present with p210 expression, but most of these cases represent lymphoid blast crises of CML. 8.5.4 12p12.3 Abnormalities Translocation t(12;21)(p12;q22), which results in the ETV6 (TEL)-AML1 (CBFA2) fusion protein, is detected in 20–25% of children with B-cell precursor ALL. This is the most common cytogenetic–molecular abnormality in childhood ALL, but is relatively uncommon in adult ALL (< 5%). Rare cases of prenatal t(12;21) have been documented, suggesting that the translocation may not be sufficient for overt leukemia and requires additional mutations (second hits) that occur after birth. Because the t(12;21)(p12;q22) translocation is not detected with conventional cytogenetic studies, FISH or RT-PCR should be used to identify this abnormality. Deletion in this region without translocation has also been reported. The ETV6-AML1 fusion protein in children with ALL is associated with an excellent prognosis, with longer event-free and overall survival [18, 20, 43, 65, 73]. 8.5.5 11q23 Abnormalities The MLL (mixed lineage leukemia) gene, located at the 11q23 locus, is involved in translocations onto other chromosomes as well as duplication. The most common MLL translocations in ALL are t(4;11)(q21;q23), t(9;11) (p21;q23), t(11;19)(q23;q13.3), and t(3;11)(q22;q23), which are associated with poor outcomes and a high incidence of myeloid marker expression [40, 69]. The ATM (ataxia telangiectasia mutated) gene, also located near chromosome 11q22-23, is frequently deleted in ALL. About 16% of pediatric ALL patients have loss of heterozygosity (LOH) at this locus. Haidar and colleagues reported that 10 of 36 (28%) adults with ALL had LOH of the ATM gene [35]. Only one (3%) of the 36 patients showed abnormalities involving chromosome 11q23 by conventional cytogenetic studies, indicating that most of these deletions are submicroscopic [35, 59]. The presence of this abnormality in adults is associated with better response to therapy [35]. 8.5.6 8q24 Abnormalities The c-myc gene is located on chromosome 8q24 and can be translocated into one of the three immunoglobulin chain loci in Burkitt leukemia: IgH on chromosome 14, Iglambda on chromosome 22, or Igkappa on chromosome 2. These translocations are detected in cytogenetic and FISH studies as t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p12;q24). Translocation of the c-myc gene into the T-cell receptor alpha/delta gene has been reported in T-cell ALL as translocation t(8;14)(q24;q11). All these translocations lead to quantitative increases in the expression of c-myc mRNA and protein, due to juxtaposition of the c-myc gene to the Ig or T-cell receptor gene enhancer. The c-myc protein activates the expression of genes necessary for cells to enter the S-phase and proliferate. This chromosomal abnormality is detected in approximately 80% of Burkitt ALL cases; mechanisms other than translocation are believed to be responsible for increased expression of the c-myc gene in the remaining cases [12, 33, 39]. 8.5.7 19p13.3 Abnormalities The E2A gene is located on chromosome 19p13.3. Translocation t(1;19)(q23;p13) forms the E2A-PBX1 fusion gene, leading to expression of the E2A-PBX1 fusion protein. This abnormality is seen in precursor B-cell ALL and is detected in approximately 5% of pediatric and 3% of adult ALL cases. A similar translocation t(17;19)(q22;p13) involving the E2A gene results in ex
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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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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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Page 105 and 106: Acute Lymphoblastic Leukemia: Clini
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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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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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