Translocation (4;11)(p12;q23) with rearrangement of FRYL and MLL in therapy-related acute myeloid leukemia

Reciprocal chromosomal translocations involving the MLL gene at chromosome region 11q23 are recurring cytogenetic abnormalities in both de novo and therapy-related acute myeloid leukemia (AML) and in acute lymphoblastic leukemia. We report a t(4;11)(p12;q23) with rearrangement of MLL and FRYL (also known as AF4p12), a human homolog to the furry gene of Drosophila, in an adult patient with therapy-related AML after fludarabine and rituximab therapy for small lymphocytic lymphoma and radiation therapy for breast carcinoma. To our knowledge, t(4;11)(p12;q23) has been reported in two previous patients, and MLL and FRYL rearrangement was demonstrated in one of them. Both of the previous patients had therapy-related leukemias after exposure to topoisomerase II inhibitors, whereas our patient had received cytotoxic therapy that did not include a topoisomerase II inhibitor. Thus, t(4;11)(p12;q23) with MLL and FRYL involvement represents a new recurring 11q23 translocation, to date seen only in therapy-related acute leukemias.     

Rare t(1;11)(q23;p15) in therapy-related myelodysplastic syndrome evolving into acute myelomonocytic leukemia: a case report and review of the literature

Balanced chromosome rearrangements are the hallmark of therapy-related leukemia that develops in patients treated with topoisomerase II inhibitors. Many of these rearrangements involve recurrent chromosomal sites and associated genes (11q23/MLL, 21q22.3/AML1, and 11p15/NUP98), which can interact with a variety of partner genes. One such rearrangement is the rare t(1;11)(q23;p15), which involves juxtaposition of the homeobox gene PMX1 (PRRX1) and NUP98. We report on an additional patient with t(1;11) who presented with myelodysplastic syndrome (MDS) subsequent to treatment for a pleomorphic liposarcoma. With time, the patient's disorder progressed to acute myelomonocytic leukemia with cytogenetic evidence of clonal evolution. To our knowledge, this is the first report of a patient presenting with a myelodysplastic syndrome with isolated t(1;11) (q23;p15), which evolved into therapy-related acute myeloid leukemia (t-AML). This patient is the third reported with this cytogenetic rearrangement and t-AML, and is compared with the other two reports of t(1;11)(q23;p15).     

Two cases of acute myeloid leukemia with t(11;17) associated with varying morphology and immunophenotype: rearrangement of the MLL gene and a region proximal to the RARalpha gene

This report describes 2 cases of acute myeloid leukemia (AML), which based on the WHO classification would be classified as AML with an 11q23 (MLL) abnormality, but with contrasting morphologic and immunophenotypic profiles. One case had monocytic features (morphologically and immunophenotypically) with a t(11;17)(q23;q21), a previously identified variant translocation in acute promyelocytic leukemia (APL). The second case had morphologic and immunophenotypic features of APL associated with a t(11;17)(q23;q25). In both cases, fluorescence-in-situ hybridization (FISH) analysis demonstrated that the 11q23 breakpoint involved the MLL gene, but RARalpha was not involved in the 17q breakpoints. These cases illustrate the importance of FISH analysis to confirm the presence of a particular recurring rearrangement.     

Chromosomal insertion involving MLL in childhood acute myeloblastic leukemia (M4)

Recurrent chromosomal rearrangements involving the 11q23 region have been described in various hematologic malignancies. Among these rearrangements, translocations are the most common mechanism involving the mixed lineage leukemia gene (MLL). Few cases of insertion have been reported and, to our knowledge, none of them involved MLL and chromosome 1. We report a complex karyotype in a childhood acute myelomonocytic leukemia (AML M4) involving the 11q23 region with an insertion between chromosomes 1 and 11 in addition to a translocation between chromosomes 11 and 22. This translocation was clarified by fluorescence in situ hybridization (FISH) analysis: 46,XY,ins(1;11)(q22q23;q13q23),t(11;22)(q13;q11q12). This finding also underlines the complementary contribution of conventional cytogenetic and FISH analysis to detect karyotypic complex abnormalities.     

Translocation (3;8)(q26;q24): a recurrent chromosomal abnormality in myelodysplastic syndrome and acute myeloid leukemia

We identified a reciprocal translocation between chromosomes 3 and 8, with breakpoints at bands 3q26 and 8q24, in five patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The t(3;8)(q26;q24) was the sole cytogenetic aberration in two patients, was associated with trisomy 13 in one patient, and occurred with monosomy 7 in two patients. In three patients, the AML or MDS developed 36, 52, and 57 months following chemotherapy for soft tissue sarcoma, mantle cell lymphoma, and diffuse large B-cell lymphoma, respectively; in these three patients, the neoplasms were considered to be therapy-related. All five patients displayed marked trilineage dysplasia and variable degrees of cytopenias, with marked thrombocytosis noted in one patient and a normal platelet count in another patient. All patients were treated with combination chemotherapy; at writing, four were still alive and one had died during a follow-up period ranging from 1 to 16 months. We conclude that the t(3;8)(q26;q24) is a recurrent translocation associated with therapy-related MDS/AML or de novo AML, and is frequently associated with monosomy 7.     

Therapy-related myelodysplastic syndrome after eradication of acute promyelocytic leukemia: cytogenetic and molecular features

The use of all trans-retinoic acid and combination chemotherapy has made acute promyelocytic leukemia (APL) a potentially curable leukemia. Late sequelae of the treatment of APL have therefore become an important consideration in the overall treatment strategy. We report a patient with APL who achieved complete clinical and molecular remission after treatment with the topoisomerase II inhibitors daunorubicin, mitoxantrone, etoposide, and the anti-metabolite cytosine arabinoside. Seven years later, she developed therapy-related myelodysplastic syndrome (t-MDS) without any evidence of relapse of the APL clone. Karyotypic and molecular cytogenetic analysis showed complex cytogenetic aberrations, including deletion of the long arm of chromosome 5, monosomy 7, but without rearrangement of the MLL gene/11q23. Interestingly, this case would be classified clinically as "epipodophyllotoxin related MDS," but pathologically as "alkylating-agent related MDS" according to the recently proposed World Health Organization (WHO) classification system for MDS. This case of t-MDS in an APL patient in durable remission highlights the importance of avoiding long-term treatment related toxicities, as APL is a potentially curable leukemia.     

Evaluation of chromosome 5 aberrations in complex karyotypes of patients with myeloid disorders reveals their contribution to dicentric and tricentric chromosomes, resulting in the loss of critical 5q regions

Dicentric chromosomes have often been observed in complex karyotypes in previously reported studies of therapy-related myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Fluorescence in situ hybridization (FISH) has now made the characterization of these rearrangements much easier. Dicentric and tricentric chromosomes were identified in 21 patients (9 MDS and 12 AML) among the 133 consecutive MDS/AML patients (17%) who had a structural or numerical aberration of chromosome 5 using conventional cytogenetic analysis. One third (7/21) of the patients had received alkylating drugs for a previously diagnosed cancer or chronic myeloproliferative disease. Loss of 5q material was identified in all 21 patients. One copy of the EGR1 (5q31) or the CSF1R (5q33 approximately q34) genes was lost in 20 of the 21 patients. Dicentric and tricentric chromosomes involving chromosome 5 are frequently observed in complex karyotypes among patients with de novo or therapy-related MDS/AML. They lead to deletions of various parts of the long arm of chromosome 5.     

A t(11;12) 11q23 leukemic breakpoint that disrupts the MLL Gene

Translocations involving 11q23 have been shown to be a consistent finding in human hematopoietic malignancies and in some constitutional abnormalities. The identification of a gene, MLL (myeloid/lymphoid or mixed-lineage leukemia), that spans the breakpoints in four different recurrent 11q23 translocations was recently reported. We describe a rare (11;12)(q23;p13) translocation, observed in leukemic cells from a patient with acute lymphoblastic leukemia, which also disrupts this gene. © 1993 Wiley-Liss, Inc.     

A new case of translocation t(6;11)(q21;q23) in a therapy-related acute myeloid leukemia resulting in an MLL–AF6q21 fusion

A new case of translocation t(6;11)(q21;q23) in a patient with therapy-related acute myeloblastic leukemia is reported. The translocation results in fusion of the MLL and AF6q21 genes. The breakpoint with AF6q21 is located within the sequences encoding the AF6q21 fork head motif. The similar location of the localization of the chromosome 6 breakpoints in the present case and in the first case reported suggests their nonrandom localization. In addition, treatment for Hodgkin's disease prior to leukemia in both t(6;11)(q21;q23) cases suggests an association of this translocation with therapy-related leukemias, as reported for the recently described t(11;16)(q23;p13.3). Genes Chromosomes Cancer 22:221–224, 1998. © 1998 Wiley-Liss, Inc.     

Molecular cytogenetic findings in a three-way novel variant of t(1;8;21)(p35;q22;q22): a unique relocation of the AML1/ETO fusion gene 1p35 in AML-M2

Acute myeloid leukemia (AML) is a malignant neoplasm of hematopoietic stem cells characterized by an abnormal proliferation of myeloid precursors, a reduced rate of apoptosis, and an arrest in cellular differentiation. The present report deals with the results of hematologic, immunophenotypic, cytogenetic, fluorescence in situ hybridization (FISH), and molecular analyses of a 53-year-old female patient diagnosed with AML-M2. Cytogenetic and FISH analysis revealed a complex translocation involving three chromosomes showing t(1;8;21)(p35;q22;q22). The observation of breakpoints at 8q22 and 21q22 suggests a rearrangement of the ETO and AML1 genes, respectively. Using a dual-color FISH test with ETO and AML1 probes, an AML1/ETO fusion signal on the derivative 1p35 instead of der(8) was demonstrated. To the best of our knowledge, this is the first report about the relocation of the AML1/ETO fusion gene to the 1p35 rather than der(8), suggesting the presence of a novel variant of t(8;21)(q22;q22) in the observed patient.     

Isochromosome 1q in a myelodysplastic syndrome after treatment for acute promyelocytic leukemia

A growing body of literature reports therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) in patients treated successfully for acute promyelocytic leukemia (APL). We report a t-MDS with an isochromosome 1q as a sole abnormality, 47,XY,+1,i(1)(q10), in a 46-year-old man with APL 14 years after he was treated with cytosine arabinosine and daunorubicin. The literature on t-MDS/t-AML after APL therapy and on isochromosome 1q is reviewed.     

Translocation (7;9)(q22;q34) in therapy-related myelodysplastic syndrome after allogeneic bone marrow transplantation for acute myeloblastic leukemia

Reciprocal translocations involving the long arm of chromosome 7 are relatively rare cytogenetic aberrations in myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). A 44-year-old woman was initially given a diagnosis of de novo AML M6A with a normal karyotype. After achieving complete remission, she received allogeneic bone marrow transplantation from an unrelated male donor. Seven months later, pancytopenia appeared with 14.8% myeloblasts and dysplastic changes of neutrophils and megakaryocytes in the bone marrow. Chromosome analysis revealed complex karyotypes, with add(7)(q22) and add(9)(q34) detected in all abnormal metaphase spreads; spectral karyotyping revealed these chromosomal aberrations to be derived from a reciprocal translocation t(7;9)(q22;q34). Fluorescence in situ hybridization analyses showed that D7S486 at 7q31 was translocated to the der(9)t(7;9), and that the ABL gene at 9q34 remained on the der(9)t(7;9). Because the same translocation reappeared and sustained for more than 8 months after second stem cell transplantation, we revised the diagnosis as therapy-related MDS after allogeneic transplantation. The t(7;9)(q22;q34) was supposed to have a crucial role in the pathogenesis of MDS. Considering two other such reported cases of AML, the t(7;9)(q22;q34) may be a novel recurrent translocation in myeloid malignancies.     

Distinct sequences on 11q13.5 and 11q23-24 are frequently coamplified with MLL in complexly organized 11q amplicons in AML/MDS patients

Amplification within chromosome arm 11q involving the mixed-lineage leukemia gene (MLL) locus is a rare but recurrent aberration in acute myeloid leukemia and myelodysplastic syndrome (AML/MDS). We and others have observed that 11q amplifications in most AML/MDS cases have not been restricted to the chromosomal region surrounding the MLL gene. Therefore, we implemented a strategy to characterize comprehensively 11q amplicons in a series of 13 AML/MDS patients with MLL amplification. Analysis of 4 of the 13 cases by restriction landmark genomic scanning in combination with virtual genome scan and by matrix-based comparative genomic hybridization demonstrated that the 11q amplicon in these four cases consisted of at least three discontinuous sequences derived from different regions of the long arm of chromosome 11. We defined a maximally 700-kb sequence around the MLL gene that was amplified in all cases. Apart from the core MLL amplicon, we detected two additional 11q regions that were coamplified. Using fluorescence in situ hybridization (FISH) analysis, we demonstrated that sequences in 11q13.5 and 11q23-24 were amplified in 8 of 13 and 10 of 12 AML/MDS cases, respectively. Both regions harbor a number of potentially oncogenic genes. In all 13 cases, either one or both of these regions were coamplified with the MLL amplicon. Thus, we demonstrated that 11q amplicons in AML/MDS patients display a complex organization and have provided evidence for coamplification of two additional regions on the long arm of chromosome 11 that may harbor candidate target genes.     

Characterization of t(11;19)(q23;p13.3) by fluorescence in situ hybridization analysis in a pediatric patient with therapy-related acute myelogenous leukemia

This case presents a Caucasian girl diagnosed with early pre-B cell acute lymphoblastic leukemia at age 2 years. The only chromosomal anomaly detected in her bone marrow cells at this time was an add(12p). By age 4 years, she had a bone marrow and central nervous system (CNS) relapse of ALL and was treated with chemotherapy that included etoposide. She was in complete remission for 2 years following chemotherapy with etoposide, but later developed therapy-related acute myeloid leukemia (t-AML). At this time, a t(11;19)(q23;p13.3) rearrangement was detected in her bone marrow cells. The AML relapsed again 1 year after allogeneic bone marrow transplant (BMT). The presence of a chromosome 11 abnormality involving band 11q23 in this patient suggests that the transformation from ALL to t-AML was a consequence of etoposide included in her chemotherapy. Studies have shown that the 11q23 breakpoint in the t(11;19) rearrangement is consistent, and involves the MLL gene in t-AML patients. However, the breakpoint in 19p is variable in that it could be located either at 19p13.1 or 19p13.3 and thus could involve either of two genes: ELL (11-19 lysine-rich leukemia gene) on 19p13.1 or ENL (11-19 leukemia gene) on 19p13.3. In this study, the t(11;19)(q23;p13.3) was further characterized and the breakpoint regions were defined by fluorescence in situ hybridization (FISH) analysis.