L3

Burkitt-cell leukemia

aIn the WHO classification, ALL and lymphoblastic lymphoma are regarded as a single entity with different clinical presentations.

bA disease with less than 20% blasts is defined as lymphoblastic lymphoma.

c"V" denotes various partner chromosomes and breakpoints.

aIn the WHO classification, ALL and lymphoblastic lymphoma are regarded as a single entity with different clinical presentations.

bA disease with less than 20% blasts is defined as lymphoblastic lymphoma.

c"V" denotes various partner chromosomes and breakpoints.

a whole chromosome (trisomy) or loss of a whole chromosome (monosomy). In many instances, molecular dissection of structural chromosomal abnormalities, especially reciprocal translocations, has identified specific genes associated with leukemogenesis. The most common structural cytogenetic aberrations and their affected genes in adult ALL are shown in Table 11.2 arranged according to their frequency.

STRUCTURAL ABERRATIONS t(9;22)(q34;q11.2)

The t(9;22)(q34;q11.2) is the single most frequent chromosomal abnormality in adult ALL, being detected in 11-34% of patients, and is associated with an unfavorable prognosis.3-11 It rarely occurs in therapy-related ALL.12 The reciprocal translocation between chromosomes 9 and 22 results in the head-to-tail fusion of variable numbers of 5' breakpoint cluster region (BCR) exons on chromosome band 22q11.2 with the exon 2 of the ABL gene (named after the Abelson murine leukemia virus), located on chromosome band 9q34.13 The protein product of the fusion gene resulting from the t(9;22) plays a central role in the development of this form of ALL. Two main types of fusion proteins, p190BCR/ABL and p210BCR/ABL, each containing NH2-ter-minal domains of BCR and COOH-terminal domains of ABL, are produced, depending on the location of the breakpoint within the BCR gene. The p190BCR/ABL product contains the first exon of BCR and occurs in 50-78% of the ALL cases with t(9;22).14-17 The p210BCR/ABL product contains either exon 13 or exon 14 of BCR and is less frequent in ALL. However, p190BCR/ABL transcripts are frequently detected at a low level in p210BCR/ABL-positive ALL.18 Clinically, there is no clear distinction between the two molecular variants of the disease,19-21 except for one report showing that the p210BCR/ABL product is associated with older age patient22 and another report demonstrating a higher risk of relapse in p190BCR/ABL ALL following allogeneic transplantation.23 Of interest, imatinib-

containing treatment has not revealed any outcome difference between the two disease types.

Secondary chromosomal aberrations accompanying t(9;22) occur in 41-86% of adult ALL patients.20'21'24-27 The most common additional aberrations in a Cancer and Leukemia Group B series27 were, in order of decreasing frequency, +der(22)t(9;22), 9p rearrangements, high hyperdiploidy (>50 chromosomes), +8, and -7. In this study, the presence of +der(22)t(9;22) was associated with a higher cumulative incidence of relapse, while the presence of -7 as a sole secondary abnormality was associated with a lower complete remission rate.27

At the molecular level, BCR/ABL has recently been shown to activate the Src kinases Lyn, Hck, and Fgr in ALL cells.28 These kinases are less frequently activated in CML, suggesting a unique downstream signaling pathway in BCR/ABL-positive ALL. Further, application of DNA microarray gene expression profiling has revealed that BCR/ABL-positive pediatric ALL is characterized by gene expression profiles distinct from other prognostically relevant leukemia subtypes. These results were recently partially confirmed and validated in samples from adult ALL patients. Finally, mutations at the ABL kinase domain are frequent and are associated with resistance to imatinib.29

The cells of almost all newly diagnosed patients with t(9;22) have a pre-B-cell immunophenotype4614; additionally, expression of CD1014 29 and of myeloid markers14 is more prevalent in patients with this translocation than in other adult ALL patients. There is some preponderance of FAB L1 over L2 morphology.6

Structural aberrations involving the short arm of chromosome 9 occur in 5-15% of adult ALL patients.6,7,9,10 They include dicentric chromosomes: dic(9;12)(p11-13;p11-13) and dic(9;20)(p11;q11), as well as deletions of 9p. Both dicentric chromosomes are associated with a favorable clinical outcome.

Table 11.2 Most frequent cytogenetic aberrations in adult ALL and their corresponding genes

Cytogenetic aberration

Genes involved3

t(4;11)(q21;q23) del(12p) or t(12p) t(14;V)(q11;V)b t(14;V)(q32;V)b del(6q)

t(1;19)(q23;p13.3) t(8;14)(q24;q32) t(2;8)(p12;q24) t(8;22)(q24;q11)

BCR/ABL 11-34

CDKN2A and CDKN2B 5-15

MLL/AF4 3-7

ETV6 4-5

TCRA and TCRD 4-6

ICH, BCL11A, TCL-1B, and CL11B 5

E2A/PBX1 3

MYC/ICH 1-2 MYC/ICK MYC/ICL

aPlease refer to text for abbreviations and references for the percentages. b"V" denotes various partner chromosomes and breakpoints.

Other anomalies of 9p, mainly del(9p), are most often associated with the presence of additional clonal aberrations (in up to 90% of patients); in almost one-third of the cases, the additional abnormalities include t(9;22).10 These data suggest that del(9p) likely represents a secondary cytogenetic abnormality.

11q23 aberrations

Chromosome band 11q23 harbors the mixed lineage leukemia gene (MLL, also known as ALL-1, HTRX, or HRX),30 which encodes a putative transcriptional regulator. MLL is involved in reciprocal translocations with many partner genes, localized on different chromosomes, both in ALL and in acute myeloid leukemia (AML).31 While the MLL gene can be amplified in a subset of AML patients, its amplification is rare in ALL.32 The distribution of 11q23/MLL translocation partners differs between ALL and AML, with t(4;11)(q21;q23) being by far the most frequent 11q23 translocation in ALL (see below). The partial tandem duplication of MLL, described in AML,33 has not been detected in ALL. 11q23/MLL translocations have been described in both de novo and therapy-related disease.34

ALL with MLL rearrangements also has a unique gene expression profile.35 Specifically, some HOX (home-obox) genes are expressed at higher levels in MLL-posi-tive ALL than in MLL-negative ALL.36 Furthermore, gene expression profiles predictive of relapse were recently identified in pediatric MLL-positive ALL in one study,37 although they did not reach statistical significance in another. Further work in this area is on going.

t(4;11)(q21;q23) The t(4;11)(q21;q23) is the most frequent chromosomal rearrangement involving the MLL gene in adult ALL, being detected in 3-7% of ALL patients, and is associated with an unfavorable out-come.3-7910 It results in two reciprocal fusion products coding for chimeric proteins derived from MLL and from a serine/proline-rich protein encoded by the AF4 (ALL1 fused gene from chromosome 4) gene.38

Griesinger et al. have demonstrated the presence of MLL/AF4 fusion gene in adult ALL patients without cytogenetically detectable t(4;11). Another study analyzed the clinical significance of the MLL/AF4 fusion gene detected molecularly in the absence of karyotypic evidence of t(4;11), and established that patients whose blasts were MLL/AF4 positive and lacked a t(4;11) had outcomes similar to patients without MLL/AF4. This study suggests that additional treatment is not needed for patients whose blasts are MLL/AF4 positive but t(4;11) negative.

Secondary cytogenetic aberrations in addition to t(4;11) are found in approximately 40% of patients.6'39'40 The most common additional changes were i(7)(q10) and +6 in one series39 and +X, i(7)(q10), and +8 in another.40 With treatment carried out according to risk-adapted therapy, no difference in outcome was observed between patients with and without clonal chromosomal aberrations in addition to t(4;11) at diagnosis,40 although this series was relatively small.

Other balanced translocations involving 11q23 Other recurrent, albeit rare in ALL, translocations involving MLL include t(6;11)(q27;q23), t(9;11) (p22;q23), t(10;11)(p12;q23), and t(11;19) (q23;p13.3).41 The respective fusion partners of the MLL gene are AF6, AF9, AF10, and ENL (eleven-nineteen leukemia). Other less common MLL partners have also been described.42 Almost all patients with 11q23 translocations have a CD10-negative and CD19-positive B-cell precursor ALL (pre-pre-B ALL).43 Coexpression of myeloid antigens is well recognized. In one series, 21 of 24 patients with CD10-/CD19+/CD15+ immunophenotype had t(4;11).20 FAB L2 morphology has been described in up to 44% of patients.6 Patients with 11q23 aberrations have an unfavorable outcome.3-10

Abnormalities of the short arm of chromosome 12 have been described in 4-5% of adult ALL patients.6,7,9,10 In one series, 20 of 23 (87%) cases with abnormal 12p had net loss of 12p material: 8 caused by deletions and 12 by unbalanced translocations.6 It is believed that a putative tumor suppressor gene is located in chromosome band 12p12.3.4445 The outcome of patients with abnormalities of 12p, who did not have t(9;22), was favorable in two adult ALL series.710

A cryptic t(12;21)(p13;q22), commonly found in pediatric ALL and also associated with a favorable outcome, is rare in adult ALL.46-48 The genes involved in this translocation are ETV649 and RUNX1 (runt-related transcription factor 1, also known as AML1 and CBFA2).50 An intriguing explanation for the favorable outcome of pediatric patients with t(12;21) may lie in the finding that the ETV6/RUNX1 protein can overcome drug resistance through transcriptional repression of multidrug resistance-1 gene expression.51 Furthermore, t(12;21) ALL is associated with a lower expression of genes involved in purine metabolism and lower de novo purine synthesis.52 Taken together, these data may explain the favorable outcome of childhood ALL with t(12;21).

t(14q11-13)

Abnormalities of the proximal part of the long arm of chromosome 14 have been described in 4-6% of adult ALL patients and are associated with the WHO precursor T-lymphoblastic leukemia/lymphoma designation. 610 The genes involved in t(14q11-13) are T-cell receptor a (TCRA) and 8 (TCRD).6

Translocations involving band 14q32, other than t(8;14)(q24;q32)

Abnormalities of the distal part of the long arm of chromosome 14 have been described in approximately 5% of adult ALL patients.10 The genes involved in t(14q32) are the immunoglobulin heavy chain locus (IGH)53 and the Krueppel zinc-finger gene (BCL11A)54 on chromosome 14q32.3, both in B-lineage ALL; the TCL1 (T-cell leukemia) gene on chromosome 14q32.155 and the distal region of a Krueppel-like zinc-finger transcription factor BCL11B (also called CTIP2) on chromosome 14q32.2,5657 both in T-lineage ALL.

del(6q)

Deletions of the long arm of chromosome 6 have been reported in 2-6% of adult ALL patients.3 6-9 58 In one large series, most deletions encompassed band 6q21 (in 20 of 23 patients), with del(6)(q12q16) being present in 3 remaining patients.6 In most patients, del(6q) is found together with additional chromosomal abnormalities.10 It is unclear whether del(6q) represents a primary or secondary cytogenetic abnormality. The outcome of patients with del(6q) was somewhat better than that of patients with a normal karyotype in one large study,6 but this finding requires confirmation.

This aberration is significantly less common in adult than in pediatric ALL. It was recognized as a separate entity in adult ALL in only one series, where it was found in 3% of the patients.6 There are two cytogenetic variants of the (1;19) translocation: a less common balanced t(1;19)(q23;p13.3) and a predominant unbalanced der(19)t(1;19)(q23;p13.3), which is almost always accompanied by two intact chromosomes 1. The genes involved in this translocation are E2A (early region of adenovirus type 2 encoding helix-loop-helix proteins E12/E47) on chromosome band 19p13.359 60 and PBX1 (pre-B-cell leukemia transcription factor 1) on chromosome band 1q23.6162 Rare ALL cases with t(1;19) lack the E2A/PBX1 fusion gene.63

The t(1;19) is associated with L1 morphology and CD10 and CD19 positivity in almost all cases.663 Interestingly, up to 25% of cases have been described to have Burkitt-like morphology, even though the immunophenotype was not always of the mature (positive surface immunoglobulin expression) type.663

This aberration and its variants, t(2;8)(p12;q24) and t(8;22)(q24;q11), are the hallmark of Burkitt lym-phoma/leukemia. As a result of t(8;14), the MYC gene, located at 8q24, is juxtaposed to the enhancer elements of the IGH gene at 14q32. In the case of variant translocations, one of the immunoglobulin light chain genes, mapped to bands 2p12 (IGK) and 22q12 (IGL), is translocated to a telomeric region of the MYC gene at 8q24.64-67 Consequently, MYC is activated and expressed at high levels. Because the product of the MYC gene, a DNA-binding protein, is implicated in the regulation of a number of other critical genes, its constitutive production results in uncontrolled proliferation of cells with one of the translocations. In approximately 45% of ALL L3 cases, one of the primary translocations, t(8;14), t(2;8), or t(8;22), is the sole chromosomal abnormality.42 The most frequent secondary aberrations include unbalanced structural anomalies of chromosome 1 that lead to gain of material from its long arm, i.e., duplications of 1q, isochromosomes of 1q, and unbalanced translocations involving 1q, and trisomies of chromosomes 7 and 8.42

The disease has two major clinical presentations: sporadic/immunodeficiency Burkitt lymphoma/ leukemia seen in the Western world, and endemic Burkitt lymphoma/leukemia found in equatorial Africa and almost always associated with Epstein-Barr virus (EBV) infection. They differ not only in regard to clinical manifestations, but also at the molecular level.68-71

Burkitt lymphoma/leukemia is associated with mature B-cell immunophenotype with surface IgM, Bcl-6, CD19, CD20, CD22, CD10, and CD79a, and is TdT, CD5, and CD23 negative.

NUMERICAL ABERRATIONS Hyperdiploidy

A high hyperdiploid karyotype, defined by the presence of more than 50 chromosomes, is detected in 2-9% of adult ALL patients.346-10 The most common extra chromosomes in 30 adult patients with high hyperdiploidy (range, 51-65 chromosomes) were (in decreasing order) 21, 4, 6, 14, 8, 10, and 17.6 In pediatric ALL, gain of the X chromosome appears to be the most common chromosomal abnormality, being detected in nearly all children with a high hyperdiploid karyotype and in up to one-third of the patients with low hyperdiploid kary-otype (i.e., 47-50 chromosomes).72 Interestingly, chromosomes 6, 8, and 10 were also the most common chromosomes lost in the hypodiploid group, along with chromosome 21. The reason for the involvement of these specific chromosomes in both types of aberrant karyotypes is unclear. Translocation (9;22) is a common structural aberration in patients with high hyper-diploidy; it was present in 11 of 30 (37%) patients in one series6 and 7 of 11 (64%) in another.26 Patients with hyperdiploidy and t(9;22) were older and had shorter disease-free survival (DFS) than those without t(9;22).6

The mechanism leading to hyperdiploidy is unknown. Several possibilities have been suggested, including polyploidization with subsequent losses of chromosomes, successive gains of individual chromosomes in consecutive cell divisions, and a simultaneous occurrence of several trisomies in a single abnormal mitosis.73

The clinical outcome of adult patients with hyper-diploid karyotypes varies in different series. In two studies, the outcome of patients with hyperdiploid kary-otypes was better than that of other adult ALL patients,3'7'9 while other studies4'6'10'26 showed poor outcome for these patients except for those with near tetraploidy.6 The reason for this discrepancy is unclear. In two studies,710 the analysis was restricted to patients with hyperdiploidy without structural abnormalities. The other studies3'4'6,9,26 did not provide information regarding structural abnormalities. A study of a larger cohort of adult ALL patients analyzing whether hyper-diploid karyotype without structural abnormalities constitutes an independent prognostic factor is warranted.

Almost all cases with high hyperdiploidy have precursor B-lineage ALL.6,74

Hypodiploidy

Hypodiploidy is defined by the presence of less than 46 chromosomes. This karyotype is found in 4-9% of adult ALL patients.3'6'7'9,75 Patients with hypodiploid karyotypes tend to be somewhat younger than patients with a normal karyotype.6,7 A recent analysis grouped patients with hypodiploidy into those with near-hap-loidy (23-29 chromosomes), low hypodiploidy (33-39 chromosomes), and high hypodiploidy (42-45 chromosomes).75 There were only six adult patients in this series, five of them in the low-hypodiploidy group and one in the high-hypodiploidy group. The most common losses in seven patients with hypodiploidy ranging from 30 to 39 chromosomes involved chromosomes 1, 5, 6, 8, 10, 11, 15, 18, 19, 21, 22, and the sex chromosomes.6 Only one study reported specifically on hypodiploidy without structural abnormalities.7 Patients with hypodiploidy have a DFS between 2 and 4 months, and therefore the abnormality is classified as unfavorable.7

Most of the patients with hypodiploidy have a B-lineage immunophenotype,6,7,75 although one report74 described up to 20% of patients with T-lineage ALL.

Trisomy 8

Trisomy 8 in ALL is most often associated with other karyotypic abnormalities; it is rare as a sole abnormality.76 Twelve of 23 (52%) patients with trisomy 8 also had t(9;22). However, patients with trisomy 8 without t(9;22) but with miscellaneous other abnormalities fared as poorly as those with trisomy 8 and t(9;22).10 It is unclear whether the adverse outcome is due to the other primary abnormalities or associated with the presence of trisomy 8 per se.

Monosomy 7

As with trisomy 8, monosomy 7 is most often associated with other karyotypic abnormalities; monosomy 7 as a sole abnormality is rare in ALL. Only one adult10 and one pediatric77 series defined patients with mono-somy 7 as a separate group. In the adult series, 9 of 14 (64%) patients with monosomy 7 had t(9;22). Patients with monosomy 7 without t(9;22) but with miscellaneous other abnormalities fared as poorly as those with monosomy 7 and t(9;22).10 It is unclear whether the adverse outcome is due to the other primary abnormalities or is associated with the presence of monosomy 7.

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