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.     

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.     

Acute lymphoblastic leukaemia.

In acute lymphoblastic leukaemia (ALL) the karyotype provides important prognostic information which is beginning to have an impact on treatment. The most significant structural chromosomal changes include: the poor-risk abnormalities; t(9;22)(q34;q11), giving rise to the BCR/ABL fusion and rearrangements of the MLL gene; abnormalities previously designated as poor-risk; t(1;19)(q23;p13), producing the E2A/PBX1 and rearrangements of MYC with the immunoglobulin genes; and the probable good risk translocation t(12;21)(p13;q22), which results in the ETV6/AML1 fusion. These abnormalities occur most frequently in B-lineage leukaemias, while rearrangements of the T cell receptor genes are associated with T-lineage ALL. Abnormalities of the short arm of chromosome 9, in particular homozygous deletions involving the tumour suppressor gene (TSG) p16(INK4A), are associated with a poor outcome. Numerical chromosomal abnormalities are of particular importance in relation to prognosis. High hyperdiploidy (51-65 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. Novel techniques in molecular cytogenetics are identifying new, cryptic abnormalities in small groups of patients which may lead to further improvements in future treatment protocols.     

Two new translocations involving the 11q23 region map outside the MLL locus in myeloid leukemias

BACKGROUND AND OBJECTIVES: In acute leukemias, chromosomal translocations involving the 11q23 band are frequently, but not invariably, associated with MLL gene rearrangement and their finding is associated with a poor prognosis. We observed two new translocations with a breakpoint in the 11q23 region at standard cytogenetic analysis: a previously undescribed t(3;11)(q21;q23) in a 70-year old woman with a fulminating form of AML-M1 and a new translocation t(6;11)(q15;q23) in a 61-year old man with an atypical chronic myelogenous leukemia. In these two patients, involvement of the MLL gene was analyzed by molecular cytogenetic techniques which also allowed a more precise mapping of the breakpoints. DESIGN AND METHODS: The MLL gene was analyzed by Southern blot and by fluorescent in situ hybridization (FISH) with a double-color MLL probe. A panel of 11q, 3q and 6q cosmid/YAC probes mapping around the breakpoints was used for breakpoint mapping. RESULTS: In both patients, FISH analysis and Southern blot showed that the MLL gene was not rearranged; in patient 1, MLL was retained on the 11q+ derivative, whereas in patient 2 it moved to the 6q- chromosome. In the t(3;11) we localized the chromosome 11 breakpoint at 11q23.3, in a region flanked by CP-939H3 and cos1p3, distal to the MLL locus; in the t(6;11) the break occurred at 11q21, in a region flanked by CP-819A5 and CP-829A6, proximal to the MLL locus. INTERPRETATION AND CONCLUSIONS: Our cases add two new translocations to the list of chromosomal anomalies involving the long arm of chromosome 11, and show that apparent translocation t(11q23) may involve loci and genes other than MLL. Characterizing the molecular heterogeneity of 11q23 translocations may identify some prognostic significance.     

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.     

11例伴t(6;11)(q27;q23)急性白血病的临床和实验研究

目的　分析伴有t(6 ;11) (q2 7;q2 3)急性白血病 (AL)的形态学、免疫学、细胞遗传学和临床特点。方法　采用骨髓细胞直接法或短期培养法制备染色体 ,用R显带技术进行核型分析 ;采用双色混合谱系白血病 (MLL)基因探针和间期荧光原位杂交 (FISH)技术 ,对其中 10例AL进行MLL重排检测 ;分别用异硫氰酸荧光素 (FITC)和得克萨斯红 (Texasred)标记的 6号和 11号全染色体涂抹探针对其中 5例标本进行染色体研究。结果　t(6 ;11)易位病例主要见于急性髓系白血病(AML) M5(8/ 11例 )。 11例t(6 ;11)AL中 9例初诊时WBC计数 (10～ 10 0 )× 10 9/L之间 ,9例有不同程度的肝、脾、淋巴结浸润。 9例为单纯t(6 ;11) ,2例伴有其他异常。进行免疫表型分析的 9例白血病中 4例髓系和淋系抗原共表达 ,除 1例外 ,其余患者均有CD3 4 表达。本组t(6 ;11)患者中位生存期为 6个月。 10例患者的双色FISH研究显示均有MLL重排 ,其中 5例标本的涂抹分析也证实 6号和 11号染色体之间发生了相互易位。结论　t(6 ;11)AL有着独特的临床特点 ,其预后不良。染色体涂抹和间期双色FISH技术是检测该易位和MLL重排的可靠手段。     

Translocation 4; 11 in acute lymphoblastic leukemia: clinical characteristics and prognostic significance

Banded bone marrow chromosome analyses have been done on 83 unselected patients with acute lymphoblastic leukemia (ALL). Seven patients, all with non-T, non-B ALL, had a translocation involving the long arms of chromosomes 4 and 11. Five of these patients, 4 children and 1 adult, were first studied at diagnosis, and the t(4;11) (q21;q23) was the only karyotypic abnormality. All 5 presented with a marked leukocytosis (greater than 150 X 10(9)/liter). Four of these 5 patients achieved a complete remission following the same intensive treatment regimen; however, remission duration and survival were very short (medians 2.5 and 8 mo, respectively). The fifth patient is currently receiving induction chemotherapy. The remaining 2 patients, both adults, were studied in relapse only, and had other karyotypic abnormalities in addition to the t(4;11). One of these relapse patients was a female whose clinical presentation and course were similar to those above. The last patient was a male who presented with a leukocyte count of 7 X 10(9)/liter and maintained an initial complete remission for 37 mo. Our data suggest that patients who have a t(4;11) (q21;q23) at the time of diagnosis of ALL have a poor prognosis with conventional therapy and require a new therapeutic approach.     

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.     

Secondary acute myeloid leukemia with translocation (4;11) and MLL/AF4 rearrangement in a 15-year-old boy treated for common acute lymphoblastic leukemia 11 years earlier

Summary Secondary acute myeloid leukemia occurring in a 15-year-old boy 11 years after initial treatment of a common lymphoblastic leukemia (c-ALL) is described. Initial complete remission was terminated after 4 years by an isolated testicular relapse, followed by first bone marrow relapse within 18 months. After he achieved remission again, an allogeneic bone marrow transplantation from his HLA-identical brother was performed. Five years and 9 months later, the patient developed thrombocytopenia, leukopenia, and anemia, but bone marrow biopsies at this time demonstrated only myelofibrosis, with no blast cell population present. A polymerase chain reaction assay of a peripheral blood sample recognized the mRNA fusion region for the MLL/AF4 rearrangement, i.e., the molecular equivalent of the translocation (4;11)(q21,q23). Four weeks later, a blast cell population with AML-M1 morphology according to the FAB classification appeared in the bone marrow, and translocation (4;11) was detected by cytogenetics. Thus, secondary leukemias with chromosomal 11q23 rearrangement can develop after a long latency period and can be diagnosed earlier with the PCR technique.     

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.     

Clonal, nonconstitutional rearrangements of the MLL gene in infant twins with acute lymphoblastic leukemia: in utero chromosome rearrangement of 11q23

Rearrangements of chromosome band 11q23 are common in infant leukemias, comprising more than 70% of the observed chromosome abnormalities in children less than 1 year of age. The MLL gene, which is located at the 11q23 breakpoint in infant, childhood, and adult acute leukemias, has been cloned and has homology to the Drosophila trithorax gene. The breakpoints in MLL are restricted to an 8.3-kilobase pair (kb) region of the gene that is involved in translocations with as many as 29 other chromosomal regions in a number of phenotypically distinct acute leukemias. We have detected an identical, clonal, nonconstitutional rearrangement of the MLL gene in peripheral blood cells from a pair of female infants twins with acute lymphoblastic leukemia (ALL) and a t(11;19)(q23;p13.3). The detection of nonidentical IGH rearrangements suggests that the MLL rearrangement took place in a B-cell precursor or hematopoietic stem cell in one twin which was transferred in utero to the other fetus resulting in ALL with an identical aneuploid karyotype in both infants. We speculate that the other MLL-related infant leukemias may also develop in utero, and that the rearrangements may occur consistently in stem cells or early precursor cells, accounting for the frequency of mixed-lineage leukemia in infants.     

Detection of chromosome 11 alterations in blood and bone marrow by interphase cytogenetics in mantle cell lymphoma

The t(11;14)(q13;q32) translocation is a consistent chromosome change in mantle cell lymphomas. This study investigates the application of fluorescent in situ hybridization (FISH) with chromosome painting probes for interphase cytogenetic analysis in patients with mantle cell lymphomas. Chromosome 11 paints have been able to show splitting of the chromosome signal consistent with the t(11; 14) translocation in interphase cells from bone marrow and blood of patients with mantle cell lymphomas. These include some in clinical remission. The chromosome probes conjugated with fluorescent molecules are hybridized with patient's DNA allowing the easy detection of chromosome 11 abnormalities with fluorescent-light microscopes. Interphase FISH has a higher sensitivity and is quicker than standard metaphase cytogenetics. This may be beneficial in rapid detection of chromosome 11 abnormalities, assisting in the diagnosis of mantle cell lymphomas. In addition, detection of a clonal population of cells is possible.     

Immunophenotype-karyotype associations in human acute lymphoblastic leukemia

The present study is a detailed analysis of the cytogenetic features of leukemic cells from 104 immunologically classified acute lymphoblastic leukemia (ALL) (78 B lineage and 26 T lineage) cases. Clonal chromosomal abnormalities were found in marrow blasts from 77 of 104 (74%) cases. Hyperdiploidy was much more frequent in B-lineage ALL cases, whereas normal diploidy was more common in T-lineage ALL cases. Fifty-nine of 104 cases (46 of 78 B-lineage ALL and 13 of 26 T-lineage ALL cases) had structural chromosomal abnormalities. Structural abnormalities involving 2p11, 7p13, 7p22, proximal q arm of 7 (7q11 or 7q22), 11q23-24, and translocations involving 12p11-13 appeared to be B-lineage specific. By comparison, structural abnormalities involving 7p15, 7q32, and 14q11 displayed T-lineage specificity. Structural abnormalities involving 9p22-p23 or 14q32, del (6)(q21-q23), del (12)(p11-p13), and the Philadelphia chromosome were found in B-lineage as well as T-lineage ALL cases. This study expands the current knowledge about immunophenotype-karyotype associations in ALL.     

Transient myeloproliferative disorder with 11q23 aberration in two neonates with Down syndrome

 Infants with Down syndrome may develop a transient myeloproliferative disorder (TMD) with the features of acute leukemia but resolving in a spontaneous remission. Chromosomal aberrations in addition to trisomy 21 have only rarely been described. In many cases of infant acute leukemia band q23 of chromosome 11 is involved in nonrandom translocations, often resulting in a rearrangement of the ALL-1 (MLL, HRX, HTRX 1) gene. Generally, this translocation carries a bad prognosis. We describe two newborn girls with Down syndrome and TMD in whom the constitutional trisomy 21 was combined with an acquired abnormality of chromosome 11. During the TMD the morphological and immunologic features were consistent with those of megakaryoblastic leukemia. The chromosome 11 abnormalities were del(11)(q23), but rearrangements of the ALL-1 gene were not found. Our patients had remissions that occurred spontaneously or after a mild chemotherapy. The important finding is that additional chromosomal changes may occur during TMD in Down syndrome. The fact that the abnormality was in region 11q23 raises the question of whether the risk for developing leukemia is increased under these conditions. Received: December 1, 1997 / Accepted: May 19, 1998     

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.     

Molecular cloning of the breakpoint of t(11;22)(q23;q11) chromosome translocation in an adult acute myelomonocytic leukaemia

Southern blot analysis with a cDNA probe of MLL indicated that the breakpoint is in a Bam HI 8.3 kb fragment which carries the exon 5–11 of MLL gene in DNA from an adult acute myelomonocytic leukaemia with a t(11;22)(q23;q11) translocation. The structural analysis of the rearranged MLL locus demonstrated that the breakpoint is localized between exon 8 and 9 of MLL locus. The normal counterpart fused to the MLL locus was proved to be derived from chromosome 22q11( AF-22 ) by somatic cell hybrids analysis and FISH. By FISH, AF-22 locus was localized to the region more centromeric to the BCR gene.     

A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in childhood acute myeloid leukemia. The UK Cancer Cytogenetics Group (UKCCG)

Partial deletion of the long arm of chromosome 5, del(5q), is the cytogenetic hallmark of the 5q-syndrome, a distinct subtype of myelodysplastic syndrome-refractory anemia (MDS-RA). Deletions of 5q also occur in the full spectrum of other de novo and therapy-related MDS and acute myeloid leukemia (AML) types, most often in association with other chromosome abnormalities. However, the loss of genetic material from 5q is believed to be of primary importance in the pathogenesis of all del(5q) disorders. In the present study, we performed fluorescence in situ hybridization (FISH) studies using a chromosome 5-specific whole chromosome painting probe and a 5q subtelomeric probe to determine the incidence of cryptic translocations. We studied archival fixed chromosome suspensions from 36 patients with myeloid disorders (predominantly MDS and AML) and del(5q) as the sole abnormality. In 3 AML patients studied, this identified a translocation of 5q subtelomeric sequences from the del(5q) to the short arm of an apparently normal chromosome 11. FISH with chromosome 11-specific subtelomeric probes confirmed the presence of 11p on the shortened 5q. Further FISH mapping confirmed that the 5q and 11p translocation breakpoints were the same in all 3 cases, between the nucleophosmin (NPM1) and fms-related tyrosine kinase 4 (FLT4) genes on 5q35 and the Harvey ras-1-related gene complex (HRC) and the radixin pseudogene (RDPX1) on 11p15.5. Importantly, all 3 patients with the cryptic t(5;11) were children: a total of 3 of 4 AML children studied. Two were classified as AML-M2 and the third was classified as M4. All 3 responded poorly to treatment and had short survival times, ranging from 10 to 18 months. Although del(5q) is rare in childhood AML, this study indicates that, within this subgroup, the incidence of cryptic t(5;11) may be high. It is significant that none of the 24 MDS patients studied, including 11 confirmed as having 5q-syndrome, had the translocation. Therefore, this appears to be a new nonrandom chromosomal translocation, specifically associated with childhood AML with a differentiated blast cell phenotype and the presence of a del(5q).