The genetics of childhood acute lymphoblastic leukaemia.

In childhood acute lymphoblastic leukaemia (ALL) a number of genetic changes have been identified which provide diagnostic and prognostic information with a direct impact on patient management. The most significant abnormalities include the translocation, t(12;21)(p13;q22), giving rise to the ETV6/AML1 gene fusion; BCR/ABL arising from t(9;22)(q34;q11); re-arrangements of the MLL gene; the E2A/PBX1 from the t(1;19)(q23;p13); re-arrangements of MYC with the immunoglobulin genes and re-arrangements of the T cell receptor genes. Chromosomal deletions, particularly those of the short arms of chromosomes 9 and 12 and the long arm of chromosome 6, have been postulated to be the sites of tumour suppressor genes (TSG). Numerical chromosomal abnormalities are of particular importance in relation to prognosis. High hyperdiploidy (50-65 chromosomes) is associated with a good risk, whereas the outlook for patients with near haploidy (23-29 chromosomes) is extremely poor. In view of the introduction of risk-adjusted therapy into the UK childhood ALL treatment trials, an interphase FISH screening programme has been developed to reveal chromosomal abnormalities with prognostic significance in childhood ALL.     

Acute lymphoblastic leukaemia: diagnosis and classification

Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease with distinct biological and prognostic groupings. Diagnosis relies on traditional cytomorphological and immunohistochemical evaluation of the leukaemic blasts. Subsequently, cytogenetic analysis identifies clonal numeric and/or structural chromosomal abnormalities that may be present, thus confirming the subtype classification and providing important prognostic information for treatment planning. The major chromosomal abnormalities in ALL are t(9;22)(q34;q11), t(12;21)(p13;q22), t(4;11)(q21;q23), t(1;19)(q23;p13), 8q24 translocations and hyperdiploidy. Generally, hyperdiploidy, occurring most frequently in paediatric cases, is associated with a good prognosis, while hypodiploidy confers a poor prognosis. Among structural chromosomal abnormalities, the t(9;22)(q34;q11) resulting in the BCR/ABL fusion protein, and rearrangements of the MLL gene, confer a poor prognosis in both children and adults, while t(12;21)(p13;q22), resulting in the TEL/AML1 fusion protein, and del (12p) confer a good prognosis. More recently, additional diagnostic and prognostic information has been gained from fluorescence in situ hybridization (FISH) and DNA microarray techniques.     

The detection and significance of chromosomal abnormalities in childhood acute lymphoblastic leukaemia

In childhood acute lymphoblastic leukaemia (ALL), cytogenetics plays an essential role in diagnosis and prediction of outcome. Conventional cytogenetic analysis, complemented by fluorescence in situ hybridization (FISH), is highly effective in the accurate detection of chromosomal abnormalities. For the precise identification of specific genetic changes, molecular techniques may be applied. Chromosomal changes in ALL may be of structural or numerical type. A large number of established structural chromosomal rearrangements have now been described for which the genetic alterations and effect on prognosis are well known. These include t(9;22)(q34;q11) and BCR/ABL, rearrangements of 11q23 involving MLL, t(12;21)(p13;q22) with the ETV6/AML1 fusion, t(1;19)(q23;p13) with E2A/PBX1, t(8;14)(q24;q32) and the immunoglobulin genes. Genetic changes associated with T ALL are also known, although their effect on outcome is less pronounced. Rare chromosomal abnormalities are continually being discovered in small patient subgroups leading to the identification of new ALL associated genetic changes. Alterations in chromosome number have a strong impact on outcome in childhood ALL. The association of a high hyperdiploid karyotype (51-65 chromosomes) with a good prognosis has been known for more than 20 years. Conversely, the loss of chromosomes in the near-haploid group (23-28 chromosomes) indicates a poor outcome. New methods of cancer classification involving gene expression profiling may eventually supercede cytogenetic analysis in the diagnosis and prediction of outcome in leukaemia. It is more likely that they will be used in a complementary approach alongside cytogenetic, FISH and molecular analysis to guide patient management in childhood ALL.     

Identification of numerical and structural chromosome aberrations in 15 high hyperdiploid childhood acute lymphoblastic leukemias using spectral karyotyping

Abstract: Spectral karyotyping (SKY) on metaphase spreads from 15 high hyperdiploid (>51 chromosomes) childhood acute lymphoblastic leukemias (ALL), which typically display a poor chromosome morphology, was performed in order to investigate the pattern of numerical abnormalities, reveal the chromosomal origin of marker chromosomes, and identify translocations and other interchromosomal rearrangements not detected by G‐banding analysis. In all cases the numerical changes could be fully characterized, and a non‐random pattern of chromosomal gain was identified, with chromosomes X, 21, 14, 17, 6, 18, 4, and 10 being most frequently gained. The numerical changes had been partly misinterpreted in 12 of the 15 ALL patients using G‐banding, and the present study hence emphasizes the importance of SKY in identifying such anomalies, some of which, i.e. +4 and +10, have been suggested to be prognostically important. The chromosomal origin of all marker chromosomes and of seven structural rearrangements, one of which was the prognostically important Philadelphia chromosome, could be identified. Five rearrangements [der( 1 )t(1;14)(q32;q21), der( 2 )t(2;8)(q36;?), der( 3 )t(2;3)(q21;?), der( 8 )t(8;14)(?;?), and t(9;21)(q12;q22)] have previously not been reported in ALL, emphasizing the value of SKY in identifying novel chromosomal rearrangements.     

Cytogenetic findings in a population-based series of 787 childhood acute lymphoblastic leukemias from the Nordic countries. The NOPHO Leukemia Cytogenetic Study Group

Different types of leukemia are characterized by different patterns of nonrandom chromosomal aberrations, but the frequencies with which the various karyotypic subtypes are seen differ among cytogenetic laboratories, countries, and geographic regions. During the 12-yr period 1986-1997, a total of 2054 children (< 15 yr of age) were diagnosed with acute lymphoblastic leukemia (ALL) in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). Cytogenetic analyses were successfully performed in 1372 patients, 787 (57%) of whom displayed clonal chromosomal abnormalities. ALL with > or = 47 chromosomes was the most frequent cytogenetic subgroup (63%), with massive hyperdiploidy (> or = 52 chromosomes) and chromosome numbers in the tri- and tetraploid range, constituting 46% of all abnormal cases. ALL-associated translocations were found at low frequencies [11q23 translocations in 3.7%, t(9;22)(q34;q11) or del(22q) in 2.2%, t(4; 11)(q21;q23) in 2.0%, t(11;19)(q23;p13) in 1.40%, t(1;19)(q23;p13) in 1.3%, and t(8;14)(q24;q32) in 1%]. Two rearrangements not previously reported in childhood ALL, but recurrent in this population-based material, were identified: der(7;9)(q10;q10) and t(9;12)(q22;p11-12), the molecular genetic consequences of which are unknown. Hyperdiploid childhood leukemias, especially those with a high hyperdiploid modal number, thus seem to be more frequent and ALL-specific translocations less frequent in the Nordic countries than in other geographic regions. Although technical differences among laboratories cannot be ruled out as a cause of at least some of the frequency differences observed compared with previous studies, systematic differences in exposure to environmental oncogenic factors or in geographic/ethnic origin are an intriguing possibility.     

Cytogenetic analysis in childhood acute lymphoblastic leukemia: experience at a single institution in Korea

We evaluated major cytogenetic abnormalities associated with childhood acute lymphoblastic leukemia (ALL) through both fluorescent in situ hybridization and conventional chromosomal analysis for 132 ALL patients diagnosed at St Mary’s Hospital in Korea. Chromosome abnormalities have been detected in 92% of patients. Eighteen (14%) patients showed numerical abnormalities only, 50 (38%) patients showed structural abnormalities only, and 53 (40%) patients showed both. The simultaneous trisomies 4, 10 and 17 were observed in 23 (17%) patients. Of the patients with abnormal karyotypes, recurrent structural abnormalities were determined in 103 (78%) cases. t(12;21)(q13;q22) was found in 29 (22%) out of 132 patients, 9p abnormalities in 13 (10%) patients, t(1;19)(q23;p13.3) in 11 (8%) patients, t(9;22)(q34;q11.2) in 11 (8%) patients, and 11q23 abnormalities in 7 (5%) patients. Interestingly, we identified five uncommon translocations such as t(5;12) (q33;p13), t(14;19)(q32;q13.1), t(12;16)(p13;q13), der(1)t(1;12)(p32;p13), and t(5;15)(p15;q11.2). Our study pool is representative of pediatric ALL patients in Korea as it consists of about 20% of patients diagnosed annually in Korea. We believe that the data provided will aid in comparative studies of the treatment outcomes, as well as the type and incidence of chromosomal abnormalities associated with childhood ALL in various Asian nations and Western countries.     

Prognostification of ALL by Cytogenetics

Cytogenetic abnormalities in chromosomal number and structure are common in pediatric ALL and some have prognostic significance. One interesting association between cytogenetic status and treatment response involves the metabolism of methotrexate. Hyperdiploid lymphoblasts accumulate increased amounts of MTX and MTX polyglutamates, and they have higher basal apoptotic rates compared with leukemic cells with lower ploidy and normal cells. These characteristics may contribute to the better outcomes observed for patients with hyperdiploid lymphoblasts. A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6–RUNX1 fusion. Others are associated with a poorer prognosis, including the Philadelphia chromosome [t(9;22)], rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21).     

Prognostic impact of karyotypic findings in childhood acute lymphoblastic leukaemia: a Nordic series comparing two treatment periods. For the Nordic Society of Paediatric Haematology and Oncology (NOPHO) Leukaemia Cytogenetic Study Group

The prognostic impact of acquired chromosome abnormalities was evaluated in a population-based consecutive series of 768 children (< 15 years of age) with acute lymphoblastic leukaemia (ALL). The study cohort included all cases of cytogenetically abnormal childhood ALL diagnosed between 1986 and 1997 in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). The probability of event-free survival (pEFS) for the total cohort was 0. 72 +/- 0.02. When comparing the two treatment periods of July 1986 to December 1991 and January 1992 to December 1997, a better survival was seen for the latter time period (pEFS of 0.69 +/- 0.02 vs. 0.76 +/- 0.02, P = 0.05). Hypodiploidy with less than 45 chromosomes, t(9;22)(q34;q11) and 11q23 translocations were associated with a dismal outcome during the whole study period (pEFS of 0.57 +/- 0.12, 0.41 +/- 0.14 and 0.37 +/- 0.10 respectively). The poor prognostic influence of 11q23 rearrangements seemed to be restricted to infants and older children (> 10 years), who differed significantly from children aged 1-10 years in this regard (P < 0. 01). Patients with t(9;22)-positive ALL seemed to benefit from allogeneic bone marrow transplantation in first remission (P = 0.05). The pEFS for children with t(1;19)(q23;p13)-positive ALL was intermediate (0.63 +/- 0.17), with a tendency to a better outcome for patients with the unbalanced variant der(19)t(1;19). Hyperdiploid ALL patients, subdivided into moderate hyperdiploidy (47-51 chromosomes), massive hyperdiploidy (52-60 chromosomes) and cases in the tri-/tetraploid range (> 60 chromosomes) had the best outcome in the last treatment period (pEFS of 0.81 +/- 0.06, 0.80 +/- 0.04 and 0.88 +/- 0.07 respectively), unless t(1;19), t(8;14), t(9;22) or 11q23 translocations were present. In a multivariate analysis including white blood cell (WBC) count, immunophenotype, age, mediastinal mass, central nervous system involvement and leukaemia karyotype, only WBC and modal chromosome number were shown to be significant independent risk factors (P < 0.01).     

Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A Collaborative Study of the Group Francais de Cytogenetique Hematologique [published erratum appears in Blood 1996 Oct 1;88(7):2818]

Cytogenetic analyses performed at diagnosis on 443 adult patients with acute lymphoblastic leukemia (ALL) were reviewed by the Groupe Francais de Cytogenetique Hematologique, correlated with hematologic data, and compared with findings for childhood ALL. This study showed that the same recurrent abnormalities as those reported in childhood ALL are found in adults, and it determined their frequencies and distribution according to age. Hyperdiploidy greater than 50 chromosomes with a standard pattern of chromosome gains had a lower frequency (7%) than in children, and was associated with the Philadelphia chromosome (Ph) in 11 of 30 cases. Tetraploidy (2%) and triploidy (3%) were more frequent than that in childhood ALL. Hypodiploidy 30-39 chromosomes (2%), characterized by a specific pattern of chromosome losses, might be related to the triploid group that evoked a duplication of the 30-39 hypodiploidy. Both groups shared similar hematologic features. Ph+ ALL (29%) peaked in the 40- to 50-year-old age range (49%) and showed a high frequency of myeloid antigens (24%). ALL with t(1;19) (3%) occurred in young adults (median age, 22 years). In T-cell ALL (T-ALL), frequencies of 14q11 breakpoints (26%) and of t(10;14)(q24;q11) (14%) were higher than those in childhood ALL. New recurrent changes were identified, ie, monosomies 7 present in Ph-ALL (17%) and also in other ALL (8%) and two new recurrent translocations, t(1;11)(p34;pll) in T- ALL and t(1;7)(q11-21;q35-36) in Ph+ ALL. The ploidy groups with a favorable prognostic impact were hyperdiploidy greater than 50 without Ph chromosome (median event-free survival [EFS], 46 months) and tetraploidy (median EFS, 46 months). The recurrent abnormalities associated with better response to therapy were also significantly correlated to T-cell lineage. Among them, t(10;14)(q24;q11) (median EFS, 46 months) conferred the best prognostic impact (3-year EFS, 75%). Hypodiploidy 30-39 chromosomes and the related triploidy were associated with poor outcome. All Ph-ALL had short EFS (median EFS, 5 months), and no additional change affected this prognostic impact. Most patients with t(1;19) failed therapy within 1 year. Patients with 11q23 changes not because of t(4;11) had a poor outcome, although they did not present the high-risk factors found in t(4;11).     

Cytogenetic and FISH studies of a single center consecutive series of 152 childhood acute lymphoblastic leukemias

Between 1977 and 1996, cytogenetic investigations were performed on 182 childhood (< or = 16 yr) acute lymphoblastic leukemias (ALL), constituting 94% (182 of 194) of all ALL patients diagnosed and treated at the Departments of Pediatrics, Lund and Malmo University Hospitals, Sweden, during these two decades. The cytogenetic analyses were successful in 152 cases (84%). The failure rate was higher for the ALL investigated before 1987 (30% vs. 4%, p < 0.0001), and also the incidence of cytogenetically normal cases was higher during 1977-86 (43% vs. 25%, p < 0.05). Clonal chromosomal abnormalities were found in 103 (68%) ALL. Structural rearrangements were detected, by chromosome banding alone, in 76 cases (50%). Fluorescence in situ hybridization (FISH) was used to identify cases with t(12;21), 11q23 rearrangements, and 9p deletions, using probes for ETV6/CBFA2, MLL, and CDKN2A/B, in 72 cases from which cells in fixative and/or unstained metaphase preparations were available. In total, the most common structural rearrangements were del(9p) (17%), t(12;21) (15%), del(6q) (8%), and MLL rearrangements (4%). Six (32%) of nineteen cytogenetically normal ALL analyzed by FISH harbored cryptic abnormalities; three displayed t(12;21) and four had del(9p), one of which also carried a t(12;21). Five (45%) of the t(12;21)-positive ALL showed +der(21)t(12;21) or ider(21)(q10)t(12;21), resulting in the formation of double fusion genes. Among the more rare aberrations, eight structural rearrangements were identified as novel recurrent ALL-associated abnormalities, and nine cases harbored rearrangements previously not reported. Sixteen cases displayed karyotypically unrelated clones at different investigations. Seven ALL (5%) showed simple chromosomal changes, unrelated to the aberrations detected at diagnosis, during morphologic and clinical remission, and in all but one instance the patients remained in remission, with the abnormal clone disappearing in subsequent investigations. This indicates that the emergence of novel clonal chromosomal aberrations during remission in childhood ALL is rather common and does not by necessity predict a forthcoming relapse.     

Acute lymphoblastic leukemias with deletion of 11q23 or a novel inversion (11)(p13q23) lack MLL gene rearrangements and have favorable clinical features

Balanced translocations affecting the 11q23 region are among the most frequent chromosomal abnormalities in childhood acute lymphoblastic leukemia (ALL), comprising 5% to 6%. These cases consistently have a rearranged MLL gene and are associated with high-risk presenting features, hyperleukocytosis and younger age, and a poor treatment outcome. To assess the clinical and biologic significance of 11q23- associated structural chromosomal abnormalities other than translocations, we studied 17 cases of childhood ALL [14 with del(11)(q23) and 3 with inv(11)(p12q23)] that were identified among 785 cases with successful chromosome analysis. In contrast to reported cases with 11q23 and MLL gene rearrangement, our series was characterized by relatively low leukocyte counts (median, 15.1 x 10(9)/L), expression of CD10 antigen but not myeloid-associated CD15 and CDw65 antigens, a relatively high frequency of T-cell immunophenotypes, and a generally favorable prognosis. All 13 cases with interpretable molecular analysis lacked MLL gene rearrangements. We suggest that most cases with deletions or inversions affecting the 11q23 region represent clinically and biologically different entities as compared with those defined by 11q23 translocation.     

Childhood B-cell acute lymphoblastic leukemia with FAB-L1 morphology and a t(9;11) translocation involving the MLL gene

The t(9;11)(p21–22;q23) translocation is frequently associated with acute monoblastic leukemia but may occasionally be seen in patients with acute lymphoblastic leukemia (ALL). We report a case of childhood ALL associated with t(9;11)(p21–22;q23) as the unique recurring chromosomal abnormality. A 3-month-old girl presented with “lymphomatous” ALL (renal enlargement), a high leukocyte count and central nervous system (CNS) involvement. Leukemic cell typing revealed a sIg+ B-cell immunophenotype without CD10 and CD34 antigenic expression while the blast cell morphology was of the FAB-L1 type. Splitting of a YAC encompassing the MLL gene was shown by fluorescence in situ hybridization (FISH) studies of the patient’s metaphase chromosomes. Rearrangement of the MLL gene was confirmed by Southern blot analysis. Despite treatment with an hyperintensive polychemotherapeutic regimen, the patient achieved a complete remission but relapsed 9 months later. These results provide further evidence that the t(9;11) may be observed in ALL, involves the MLL gene and is associated with a poor outcome. Moreover, this observation clearly illustrates that sIg+ B-cell ALL is not necessarily associated with a Burkitt (L3) morphology.     

An analysis of leukemic cell chromosomal features in infants

Leukemic cell chromosomal findings in 27 infants were analyzed. Among the 18 cases of acute nonlymphoblastic leukemia (ANLL), all but two were classified as monocytic or myelomonocytic. The remaining nine cases were acute lymphoblastic leukemia (ALL), seven lacking the common ALL antigen and two having cytoplasmic immunoglobulin (pre-B phenotype). Twenty-five cases (93%) had an abnormal karyotype, 21 (84%) being pseudodiploid. Chromosomal translocations were detected in 67% of the ANLL cases and in 78% of the ALL cases. Nonrandom chromosomal abnormalities included the t(9;11)(p21-22;q23) in three cases of monocytic leukemia, inversion of chromosome 16 in three cases of myelomonocytic leukemia with bone marrow eosinophilia, and t(4;11)(q21;q23) in one case of ALL. Chromosomal regions preferentially involved in infant leukemia included 11q23-25 (13 cases), 9p21-22 and 10p11-13. All but one of the 24 cases with chromosomal breakage or rearrangement had breakpoints that corresponded to known fragile sites, half of which were at 11q23-25, a finding that may have pathogenetic importance. The CALLA- or pre-B phenotype and the presence of chromosomal translocations in most infants with ALL provide a biological explanation for their poor prognosis.     

Prognostic value of cytogenetics in adult patients with Philadelphia-negative acute lymphoblastic leukemia

The prognostic value of cytogenetics in adult acute lymphoblastic leukemia (ALL) is not as established as in childhood ALL. We have analyzed the outcome and prognostic value of karyotype in 84 adults diagnosed with Philadelphia-negative ALL from a single institution that received induction chemotherapy and had successful karyotype performed. The most frequent finding was normal karyotype in 35 (42%) cases, followed by aneuploidies in 20 cases (24%) and t(4;11)(q21;q23)/MLL/AF4 in 5 (6%), and the remaining 24(27%) cases carried miscellaneous clonal abnormalities. The group of patients with t(4;11)(q21;q23)/MLL/AF4, hypodiploidy and low hyperdiploidy (less than 50 chromosomes) showed a worse outcome than those with normal karyotype and miscellaneous abnormalities in terms of overall survival (OS) (3 years OS; 47% vs. 13%, p?=?0.014) and relapse-free survival (RFS) (3 years RFS; 44% vs. 27%, p?=?0.005). Other cytogenetic prognostic classifications reported to date were tested in our series, but any was fully reproducible. In conclusion, karyotype is a useful tool for risk assessment in adult ALL. We have confirmed the bad prognosis of t(4;11)(q21;q23)/MLL/AF4 and hypodiploidy. Besides, low hyperdiploidy could also define a high-risk group of patients who might be candidates for more intensive treatment.     

IGH@ translocations co-exist with other primary rearrangements in B-cell precursor acute lymphoblastic leukemia

Primary established genetic abnormalities in B-cell precursor acute lymphoblastic leukemia include high hyperdiploidy (51–65 chromosomes), the translocations t(12;21)(p13;q22)/ETV6-RUNX1 fusion and t(9;22)(q34;q11)/BCR-ABL1 fusion, MLL rearrangements and intrachromosomal amplification of chromosome 21. These rearrangements are of prognostic and therapeutic relevance and are usually mutually exclusive. We identified 28 patients at diagnosis with both a primary genetic rearrangement and an immunoglobulin heavy chain locus translocation using chromosomal analysis and fluorescence in situ hybridization. Among these patients, the immunoglobulin heavy chain locus translocation partner gene was identified in six (CRLF2, CEBPA, CEBPB, TRA/D@, IGF2BP1 and IGK@). Clonal architecture was investigated in 17 patients using multiple color interphase fluorescence in situ hybridization analysis, which showed that the translocation was acquired as a secondary abnormality in ten patients, in four patients the etiology was undetermined and in three patients it was observed in a separate clone from the primary chromosomal rearrangement. These findings demonstrate the co-existence of immunoglobulin heavy chain locus translocations with other primary chromosomal rearrangements either in the same or separate clones, which may have prognostic significance in B-cell precursor acute lymphoblastic leukemia. Clinical trials: UKALLXII: Study ID n. ISRCTN77346223 and ALL2003: Study ID n. ISRCTN07355119     

Genetics of small lymphocyte disorders.

Cytogenetic analysis of small lymphocytes disorders is hindered by the low mitotic activity of the malignant cells. The use of fluorescence in situ hybridization (FISH) allows the detection of chromosomal amplifications, deletions, or translocations at a single-cell level in dividing and resting cells. The use of FISH in combination with other molecular techniques has defined the deletion in band 13q14 as the most common abnormality in chronic lymphocytic leukemia, followed by del (11)(q22-23), trisomy 12, del (17)(p13), and del (6)(q21). The del 13q14 is also found in 70% of mantle-cell lymphomas (MCLs) and in non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) patients. These findings point to the existence of yet unidentified tumor-suppressor gene(s) at the 13q14 locus, the loss/inactivation of which leads to B-cell neoplasia. Del (17(p13) (involving the p53 tumor-suppressor gene) and del (11)(q22-23) (involving the ataxia-telangiectasia gene [ATM]) seem to be independent prognostic factors for poor survival in chronic lymphocytic leukemia (CLL) patients. In MCL, the t(11;14) involving the bcl-1 gene is found, but data from a bcl-1 transgenic animal model suggest that hyperexpression of bcl-1 is not sufficient for lymphomatogenesis. Similar data are observed in bcl-2 transgenic animals, a finding showing that the bcl-2 hyperexpression observed in t(14;18)-positive follicular lymphoma cells is not sufficient to confer a malignant phenotype. The contribution of other chromosomal abnormalities other than bcl-1 and bcl-2 rearrangements in the pathogenesis of MCL and follicular-cell lymphomas has to be determined.     

Cytogenetic abnormalities in childhood acute myeloid leukaemia: a Nordic series comprising all children enrolled in the NOPHO-93-AML trial between 1993 and 2001

Between 1993 and 2001, 318 children were diagnosed with acute myeloid leukaemia (AML) in the Nordic countries. The patient group comprised 237 children < 15 years of age with de novo AML, 42 children < 15 years with Down syndrome (DS) and de novo AML, 18 adolescents 15-18 years of age with de novo AML, and 21 children < 15 years with treatment-related AML (t-AML). The first group was all-inclusive, yielding an annual childhood de novo AML incidence of 0.7/100 000. Cytogenetic analyses were successful in 288 cases (91%), and clonal chromosomal abnormalities were detected in 211 (73%). The distribution of ploidy levels were pseudodiploidy (55%), hyperdiploidy (34%) and hypodiploidy (11%). The most common aberrations (> 2%) were + 8 (23%) (as a sole change in 6.2%), 11q23-translocations, including cryptic MLL rearrangements (22%) [t(9;11)(p21-22;q23) in 11%], t(8;21)(q22;q22) (9.0%), inv(16)(p13q22) (6.2%), -7/7q- (5.2%), and t(15;17)(q22;q12) (3.8%). Except for +8, these abnormalities were rare in group 2; only one DS patient had a t(8;21) and none had 11q23-translocations, t(15;17) or inv(16). In the t-AML group, three cases displayed 11q23-rearrangements, all t(9;11); and there were no t(8;21), t(15;17) or inv(16). Overall, the observed frequencies of t(8;21) and t(15;17) were lower, and frequencies of trisomy 8 and 11q23-translocations higher, than in previous studies. Furthermore, seven abnormalities that were previously reported as only single AML cases were also seen, meaning that der(4)t(4;11)(q26-27;q23), der(6)t(1;6)(q24-25;q27), der(7)t(7;11)(p22;q13), inv(8)(p23q11-12), t(11;17)(p15;q21), der(16)t(10;16)(q22;p13) and der(22)t(1;22)(q21;q13) are now classified as recurrent abnormalities in AML. In addition, 37 novel aberrations were observed, 11 of which were sole anomalies.     

Childhood B-cell acute lymphoblastic leukemia with FAB-L1 morphology and a t(9;11) translocation involving the MLL gene

The t(9;11)(p21–22;q23) translocation is frequently associated with acute monoblastic leukemia but may occasionally be seen in patients with acute lymphoblastic leukemia (ALL). We report a case of childhood ALL associated with t(9;11)(p21–22;q23) as the unique recurring chromosomal abnormality. A 3-month-old girl presented with lymphomatous ALL (renal enlargement), a high leukocyte count and central nervous system (CNS) involvement. Leukemic cell typing revealed a sIg+ B-cell immunophenotype without CD10 and CD34 antigenic expression while the blast cell morphology was of the FAB-L1 type. Splitting of a YAC encompassing the MLL gene was shown by fluorescence in situ hybridization (FISH) studies of the patients metaphase chromosomes. Rearrangement of the MLL gene was confirmed by Southern blot analysis. Despite treatment with an hyperintensive polychemotherapeutic regimen, the patient achieved a complete remission but relapsed 9 months later. These results provide further evidence that the t(9;11) may be observed in ALL, involves the MLL gene and is associated with a poor outcome. Moreover, this observation clearly illustrates that sIg+ B-cell ALL is not necessarily associated with a Burkitt (L3) morphology.