Abnormalities of the long arm of chromosome 21 in 107 patients with hematopoietic disorders: a collaborative retrospective study of the Groupe Français de Cytogénétique Hématologique

doi:10.1016/j.cancergencyto.2005.08.005

Cancer Genetics and Cytogenetics

Volume 166, Issue 1, 1 April 2006, Pages 1-11

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Abstract

Chromosome 21 is frequently rearranged in hematopoietic malignancies. In order to detect new chromosomal aberrations, the Groupe Français de Cytogénétique Hématologique collected a series of 107 patients with various hematologic disorders and acquired structural abnormalities of the long arm of chromosome 21. The abnormalities were subclassified into 10 groups, according to the location of the 21q breakpoint and the type of abnormality. Band 21q22 was implicated in 72 patients (excluding duplications, triplications, and amplifications). The involvement of the RUNX1 gene was confirmed in 10 novel translocations, but the gene partners were not identified. Eleven novel translocations rearranging band 21q22 with bands 1q25, 2p21, 2q37, 3p21, 3p23, 4q31, 6p24∼p25, 6p12, 7p15, 16p11, and 18q21 were detected. Rearrangements of band 21q11 and 21q21 were detected in six novel translocations with 5p15, 6p21, 15q21, 16p13, and 20q11 and with 1p33, 3q27, 5p14, 11q11, and 14q11, respectively. Duplications, triplications, amplifications, and isodicentric chromosomes were detected in eight, three, eight, and three patients, respectively. The present study shows both the wide distribution of the breakpoints on the long arm of chromosome 21 in hematopoietic malignancy and the diversity of the chromosomal rearrangements and the hematologic disorders involved. The findings invite further investigation of the 21q abnormalities to detect their associated molecular rearrangements.

Introduction

Abnormalities of the long arm of chromosome 21 are common in hematopoietic malignancies. Recurrent translocations involving the chromosomal band 21q22 and particularly the RUNX1 gene (previous symbols: AML1 and CBFA2) are among the most common acquired translocations in patients with acute leukemia. Other 21q rearrangements with other localization breakpoints have been less extensively studied. The Groupe Français de Cytogénétique Hématologique (GFCH) decided to collect a series of patients with malignant hematopoietic disorders and 21q rearrangements in order to (a) identify abnormalities not involving RUNX1 and (b) find new abnormalities of this promiscuous gene.

Section snippets

Patients

The criteria for inclusion in the retrospective study of the GFCH were the detection of acquired structural 21q rearrangement in patients with hematopoietic malignancy excluding malignant lymphoma. Common translocations, t(8;21)(q22;q22) and t(12;21)(p13;q22), were also excluded, as well as the i(21)(q10) abnormality.

A total of 107 eligible patients from 19 French and Belgian centers were included in the study (see Appendix). Cytological characterization of the disorders was performed in every

Patients

Cases were collected from a total of 107 patients (38 female, 69 male), ranging in age from 2 to 92 years (median: 53 years). The distribution of the hematopoietic disorders shows that myeloid disorders were prominent (92 versus 15 lymphoid) and that only 11 children, defined as under 16 years, were included (Table 1)

The patients were distributed into 10 groups according to the localization of the chromosomal breakpoint and the type of the chromosome rearrangement (Table 2 and Table 3, Table 4,

Discussion

Rearrangements of band 21q22 are the most frequent abnormalities of chromosome 21 structural abnormalities occurring in hematopoietic disorders. The two most frequent translocations of acute leukemia, t(8;21)(q22;q22) and t(12;21)(p13;q22), result in the fusion of the RUNX1 gene to RUNX1T1 (previously CBFA2T1; alias ETO) and ETV6 (alias TEL), respectively. Band 21q22, where RUNX1 is located, is involved in at least 40 other chromosome bands in other less common acquired translocations, and the

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Cited by (27)

Prognostic impact of t(16;21)(p11;q22) and t(16;21)(q24;q22) in pediatric AML: A retrospective study by the I-BFM study group
2018, Blood
Citation Excerpt :
Surprisingly, even patients with secondary AML did not suffer from relapse. To date, 24 RUNX1-CBFA2T3 cases have been reported, of whom only 5 were pediatric.15,16,20,32-45 In the literature, these patients were considered to be high risk.
To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 × 10⁹/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American-British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS-ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk.
CLCA2, a novel RUNX1 partner gene in a therapy-related leukemia with t(1;21)(p22;q22)
2010, Cancer Genetics and Cytogenetics
Citation Excerpt :
RUNX1 acts as a key regulator of hematopoiesis and is frequently targeted by mutations and chromosomal translocations in leukemias [2]. RUNX1 is rearranged in more than 30 different chromosomal translocations in a spectrum of hematological malignancies [3]. Most of them, including the recurrent t(12;21)(p13;q22), generate in-frame fusion transcripts that encode chimeric proteins.
The RUNX1 gene is frequently rearranged in de novo and therapy-related leukemia. In the present study, we identified the CLCA2 gene as a novel fusion partner of RUNX1 in a case of therapy-related acute myeloid leukemia associated with t(1;21)(p22;q22). Reverse transcriptase–polymerase chain reaction analysis and sequencing revealed that the t(1;21) results in out-of-frame RUNX1-CLCA2 fusions. Alternative splicing generates at least six fusion transcripts, including a major transcript fusing RUNX1 exon 6 with CLCA2 exon 2. These out-of-frame fusions produce putative truncated RUNX1 isoforms retaining the DNA binding Runt domain but not the transcriptional regulatory domain of RUNX1. No mutations were found in the exons encoding the Runt and C-terminal domains of the nonrearranged RUNX1 gene. Similar to truncated RUNX1 isoforms previously described, these shortened products could act as dominant negative inhibitors of RUNX1-dependent transactivation. CLCA2 is a breast tumor suppressor gene that encodes a member of the calcium-activated chloride channel family and is involved for the first time in a chromosomal translocation. The RUNX1-CLCA2 fusion is another example of out-of-frame fusion generating truncated RUNX1 isoforms that represent a recurrent molecular mechanism in RUNX1-related leukemias.
An unbalanced t(15;18)(q21-q22;p11) as the sole cytogenetic aberration in a patient with B-cell chronic lymphocytic leukemia
2010, Cancer Genetics and Cytogenetics
t(3;21)(q22;q22) leading to truncation of the RYK gene in atypical chronic myeloid leukemia
2009, Cancer Letters
Citation Excerpt :
Interestingly, in two of the three cases of idiopatic myelofibrosis the t(3;21) was the sole chromosomal aberration, whereas in the third, a del(20)(q?) was also present [30–32]. Two more cases showed the t(3;21) as the sole abnormality, an AML NOS with two related clones of which the original one had only the 3;21-translocation [33], and an AML M4 presenting two unrelated clones, one with the t(3;21) and the second with a t(11;17) [34].
The analysis of a small number of patients with atypical chronic myeloid leukemia showing balanced chromosomal translocations has revealed diverse tyrosine kinase fusion genes, most commonly involving FGFR1, PDGFRA, PDGFRB, JAK2, and ABL. We present a case of aCML with a 3q22;21q22-translocation that led to truncation of the receptor-like tyrosine kinase (RYK) gene and its juxtaposition with sequences from chromosome 21 including the ATP5O gene coding for a mitochondrial ATP synthase. The resulting fusion was not in frame, however, which is why we speculate that an abrogated RYK gene product rather than a chimeric protein might be the leukemogenic result.
RUNX1-MTG16 fusion gene in acute myeloblastic leukemia with t(16;21)(q24;q22): case report and review of the literature
2008, Cancer Genetics and Cytogenetics
We report here a 73-year old female who was admitted for hematomas, dyspnea, and fever. Hematological data showed pancytopenia with 9% blast cells positive for CD13, CD33, CD34, HLAD2, and myeloperoxydase. A diagnosis of acute myeloid leukemia (AML) type 2 (FAB classification) was made. Banding cytogenetic techniques performed on bone marrow cells showed a 48,XX,+8,+9,del(9)(q22q33)x2 ,t(16;21)(q24;q22)[20]/46,XX[2] karyotype. Fluorescence in situ hybridization (FISH) with BACs covering the RUNX1 (alias AML1) (band 21q22) and MTG16 (band 16q24) gene showed a fusion of both genes. The t(16;21)(q24;q22) has been described in 16 AML cases, including ours. Eleven patients had received chemotherapy for a previous cancer, most of them were been treated with DNA-topoisomerase II inhibitors known to be associated with chromosomal translocations involving the RUNX1 gene. The significant homology between MGT16 and MTG8 suggests that the RUNX1-MTG16 fusion gene induced by the t(16;21)(q24;q22) is a variant of the RUNX1-MTG8 that shares similar activity.
Multiple copies of RUNX1: description of 14 new patients, follow-up, and a review of the literature
2008, Cancer Genetics and Cytogenetics
Citation Excerpt :
We summarized the clinical and laboratory characteristics, gender, age, WBC, immunophenotype, and RUNX1 copy number of the 86 patients in Fig. 2. The karyotypes of the 86 patients revealed abnormalities in addition to add(21)(q22) in all chromosomes except for number 2, as shown in Fig. 3 [1–4,7–22]. As described previously [2], trisomy X was the most frequent numerical abnormality.
RUNX1 over-representation is present in children with acute lymphoblastic leukemia. Although these cases have been related with poor outcome, not all reports describe patient follow-up. To understand its associated clinical features and prognosis, we report on 14 children with ALL and RUNX1 over-representation with laboratory data and outcomes compared to previous reports. Eighty-six children with RUNX1 over-representation have been described, including the 14 patients of this study. Most of them are between 6 and 15 years of age, have low leukocyte counts, pre-B immunophenotype, and three to eight RUNX1 copies. Of the 69 patients with follow-up data, 21 of them relapsed or died, suggesting that RUNX1 over-representation is associated to a poor outcome.

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¹: The remaining participants in Groupe Français de Cytogénétique Hématologique (GFCH) are listed in the Appendix, along with the number of patients for each center.

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Cancer Genetics and Cytogenetics

Abstract

Introduction

Section snippets

Patients

Patients

Discussion

References (19)

Translocation (8;21) and its variants in acute nonlymphocytic leukemia: the relative importance of chromosomes 8 and 21 to the genesis of the disease

Cancer Genet Cytogenet

The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8 (ETO) family

Blood

Hyperdiploid (47–50) acute lymphoblastic leukemia in children

Blood

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

Blood

Cytogenetic and fluorescence in situ hybridization analyses of hematologic malignancies in Korea

Cancer Genet Cytogenet

Detection of clonal karyotypic abnormalities in most patients with acute nonlymphocytic leukemia examined using short-term culture techniques

Cancer Genet Cytogenet

ISCN 1995: an international system for human cytogenetic nomenclature (1995)

A new chromosome translocation (3;21) in M2 acute lymphocytic leukemia

Acta Haematol

Cited by (27)

Prognostic impact of t(16;21)(p11;q22) and t(16;21)(q24;q22) in pediatric AML: A retrospective study by the I-BFM study group

CLCA2, a novel RUNX1 partner gene in a therapy-related leukemia with t(1;21)(p22;q22)

An unbalanced t(15;18)(q21-q22;p11) as the sole cytogenetic aberration in a patient with B-cell chronic lymphocytic leukemia

t(3;21)(q22;q22) leading to truncation of the RYK gene in atypical chronic myeloid leukemia

RUNX1-MTG16 fusion gene in acute myeloblastic leukemia with t(16;21)(q24;q22): case report and review of the literature

Multiple copies of RUNX1: description of 14 new patients, follow-up, and a review of the literature

Lead articleAbnormalities of the long arm of chromosome 21 in 107 patients with hematopoietic disorders: a collaborative retrospective study of the Groupe Français de Cytogénétique Hématologique

Abstract

Introduction

Section snippets

Patients

Patients

Discussion

Cancer Genet Cytogenet

Blood

Blood

Blood

Cancer Genet Cytogenet

Cancer Genet Cytogenet

ISCN 1995: an international system for human cytogenetic nomenclature (1995)

A new chromosome translocation (3;21) in M2 acute lymphocytic leukemia

Acta Haematol

Lead article
Abnormalities of the long arm of chromosome 21 in 107 patients with hematopoietic disorders: a collaborative retrospective study of the Groupe Français de Cytogénétique Hématologique