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.     

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.     

MLL-CBP fusion transcript in a therapy-related acute myeloid leukemia with the t(11;16)(q23;p13) which developed in an acute lymphoblastic leukemia patient with Fanconi anemia

We describe a boy with Fanconi anemia (FA) who developed acute lymphoblastic leukemia (ALL) (FAB-LI) followed by acute myeloid leukemia (AML) (FAB-M5) at relapse. The patient was diagnosed with early pre-B-cell ALL without preceding aplastic anemia and was treated with ALL-oriented chemotherapy which included doxorubicin (a total dose of 140 mg/m(2) administered), which is a topoisomerase II inhibitor. Complete remission was obtained, but after 38 weeks AML developed. The karyotype of ALL cells at diagnosis showed 46,XY, and that of AML cells at relapse was 46,XY, t(11;16)(q23;p13). An MLL gene rearrangement and MLL-CBP chimeric mRNA were found in AML, but not in ALL. A diagnosis of FA was confirmed by an increased number of chromosomal breaks and rearrangements in peripheral blood lymphocytes cultured with mitogen in the presence of mitomycin C. We conclude that this FA patient developed ALL followed by a therapy-related t(11;16)-AML resulting in an MLL-CBP fusion. Further examination of such patients would shed light on leukemogenesis in FA patients. Genes Chromosomes Cancer 27:264-269, 2000.     

MLL rearrangement with t(6;11)(q15;q23) as a sole abnormality in a patient with de novo acute myeloid leukemia: conventional cytogenetics, FISH, and multicolor FISH analyses for detection of rare MLL-related chromosome abnormalities

We report a rare case of acute myeloid leukemia (AML) with t(6;11)(q15;q23) in a 50-year-old female showing a poor prognosis. Bone marrow biopsy revealed markedly hypercellular marrow with infiltrates of myeloblasts, consistent with AML-M2 morphology. The karyotype of this patient was 46,XX,t(6;11)(q15;q23) in all analyzed cells, and the results of fluorescence in situ hybridization (FISH) and multi-color FISH analysis confirmed this unique MLL rearrangement as a sole abnormality. To our knowledge, t(6;11)(q13 approximately q15;q23) is the most rare type of MLL rearrangement involving the long arm of chromosome 6. Only two cases with t(6;11)(q13;q23) and three cases with t(6;11)(q15;q23) have been reported, but detailed clinical or laboratory data were not available. From this report, it is apparent that in a cytogenetic laboratory, the accurate detection of a rare type of MLL rearrangement is very important in the differential diagnosis, prompt treatment, and prediction of prognosis of leukemias.     

Pediatric T-cell acute lymphoblastic leukemia with aberrations of both MLL loci

Translocations involving the MLL gene at 11q23 have been implicated in acute lymphoblastic leukemia (ALL), as well as acute myeloid leukemia (AML). Such translocations result in gain of function fusion proteins that drive cell proliferation. Except in cases of T-cell ALL, MLL rearrangement is typically associated with a poor prognosis. We report a case of T-cell ALL with a t(11;19)(q23;p13.3) and deletion of the other chromosome 11 homolog at band q23. Fluorescence in situ hybridization (FISH) analyses confirmed involvement of the MLL loci in both the translocation and deletion. This case is unique in that deletions of 11q23 reported in ALL generally do not involve MLL. We are unaware of a previous report showing rearrangement of the MLL loci on both chromosome 11 homologues.     

Analysis of t(9;11) chromosomal breakpoint sequences in childhood acute leukemia: almost identical MLL breakpoints in therapy-related AML after treatment without etoposides

The translocation t(9;11)(p22;q23) is a recurring chromosomal abnormality in acute myeloid leukemia (AML) fusing two genes designated as MLL and AF9. Within MLL, almost all rearrangements cluster in an 8.3-kb restricted region and fuse 5' portions of MLL to a variety of heterologous genes in various 11q23 translocations. AF9 is one of the most common fusion partners of MLL. It spans more than 100 kb, and two breakpoint cluster regions (BCRs) have been identified in a telomeric region of intron 4 (BCR1) and within introns 7 and 8 (BCR2). We investigated 11 children's bone marrow or peripheral blood samples (3 AML, 5 t-AML, 2 ALL, 1 ALL relapse) and two cell lines (THP-1 and Mono-Mac-6) with cytogenetically diagnosed translocations t(9;11). By use of an optimized multiplex nested long-range PCR assay, a breakpoint-spanning DNA fragment from each sample was amplified and directly sequenced. In four patients and two cell lines, the AF9 breakpoints were located within BCR1 and in two patients within BCR2, respectively. However, in five patients the AF9 breakpoints were found outside the previously described BCRs within the centromeric region of intron 4 and even within intron 3 in one case. All five patients with a secondary AML, who had not received etoposides during treatment of the primary malignant disease, revealed almost identical MLL breakpoints very close to a breakage hot spot inducible by topoisomerase II inhibitors or apoptotic triggers in vitro. Sequence patterns around the breakpoints indicated involvement of a "damage-repair mechanism" in the development of t(9;11) similar to t(4;11) in infants' acute leukemia.     

Infant acute lymphoblastic leukemia with t(11;16)(q23;p13.3) and lineage switch into acute monoblastic leukemia

Rearrangements of the mixed-lineage leukemia (MLL) gene have been associated with a poor prognosis in infant acute lymphoblastic leukemia (ALL). Previously, MLL translocations involving the CREP-binding protein (CREBBP) gene at chromosome band 16p13.3 have primarily been reported in treatment-related acute myeloid leukemia, after chemotherapy for other primary malignancies using topoisomerase II inhibitors. We report a case of de novo infant ALL with t(11;16)(q23;p13.3). After chemotherapy, this patient developed an acute monoblastic leukemia (M5b) with retention of the t(11;16)(q23;p13.3), indicating that this is a lineage switch of the original leukemic clone. To our knowledge, these findings have not been previously reported.     

Rearrangement of the MLL gene and a region proximal to the RARalpha gene in a case of acute myelocytic leukemia M5 with a t(11;17)(q23;q21)

A case of acute myelocytic leukemia (AML) M5 subtype (French-American-British classification), in a 13-year-old girl showed the abnormal karyotype 46,XX,t(11;17)(q23;q21) in all bone marrow cells analyzed. Rearrangements involving 11q23 are frequent in cases of AML M5 and often involve the MLL gene. Nevertheless, t(11;17)(q23;q21) is very rare in this type of leukemia. In acute promyelocytic leukemia, the RARalpha gene, located at 17q21, is involved in almost all cases. Fluorescence in situ hybridization studies revealed a deletion of the C-terminal part of the MLL gene and a translocation of the RARalpha gene on the derivative chromosome 11, proximal to the remaining part of the MLL gene. However, hybridization with the LSI RARA dual color break-apart rearrangement probe showed that the RARalpha gene was not rearranged in this translocation. This is the first study reporting a t(11;17)(q23;q21) with a deletion distal to MLL gene exon 6 in a case of AML M5. Furthermore, this is the second study that strongly suggests the implication of a gene proximal and close to the RARalpha locus in a case of AML M5. According to these results, the discovery of new fusion partner genes of MLL and the precise characterization of t(11;17) will be important for the understanding of neoplastic cell differentiation in AML M5.     

Characterization of genomic breakpoints in MLL and CBP in leukemia patients with t(11;16)

The recurring chromosome translocation t(11;16)(q23;p13) is detected in leukemia patients, virtually all of whom have received previous chemotherapy with topoisomerase (topo) II inhibitors. In the t(11;16), 3' CBP, on 16p13, is fused to 5' MLL, on 11q23, resulting in an MLL-CBP fusion gene that plays an important role in leukemogenesis. In this study, we cloned genomic breakpoints of the MLL and CBP genes in the t(11;16) in the SN-1 cell line and in five patients with therapy-related leukemia, all of whom had received topo II inhibitors for previous tumors. In all patients except one, both the genomic MLL-CBP and the reciprocal fusions were cloned. Genomic breakpoints in MLL occurred in the 8.3-kb breakpoint cluster region in all patients, whereas the breakpoints in CBP clustered in an 8.2-kb region of intron 3 in four patients. Genomic breakpoints in MLL occurred in intron 11 near the topo II cleavage site in the SN-1 cell line and in one patient, and they were close to LINE repetitive sequences in two other patients. In the remaining two patients, genomic breakpoints were in intron 9 in Alu repeats. Genomic breakpoints in CBP occurred in and around Alu repeats in one and two patients, respectively. In two patients, the breaks were near LINE repetitive sequences, suggesting that repetitive DNA sequences may play a role. No specific recombination motifs were identified at or near the breakpoint junctions. No topo II cleavage sites were detected in introns 2 and 3 of CBP. However, there were deletions and duplications at the breakpoints in both MLL and CBP and microhomologies or nontemplated nucleotides at most of the genomic fusion junctions, suggesting that a nonhomologous end-joining repair mechanism was involved in the t(11;16).     

Translocation (10;11)(p13;p15) in an infant acute myeloid leukemia with MLL gene rearrangement.

Molecular rearrangements of the MLL gene at the 11q23 region have been identified in most cases of infant leukemia, regardless of the phenotype. We present a case of acute myeloid leukemia which coexpressed myeloid and lymphoid markers in a 12-month-old girl. Karyotype analysis revealed the presence of a thus far unreported translocation t(10;11)(p13;p15). Although no 11q23 abnormalities were cytogenetically detectable, an MLL gene molecular rearrangement was found.     

C/EBPbeta suppression by interruption of CUGBP1 resulting from a complex rearrangement of MLL

Translocations involving the mixed-lineage leukemia gene (MLL) confer a poor prognosis in acute leukemias. In t(1;11)(q21;q23), MLL is fused reciprocally with AF1q. Here we describe a t(1;11)(q21;q23) with a secondary event involving insertion of the telomeric portion of MLL into the p arm of chromosome 11 (11p11). We show that this latter event interrupts the CUG triplet repeat binding protein-1 (CUGBP1) gene, a translational enhancer of C/EBPbeta. We then showed that these cells have reduced expression of CUGBP1 and C/EBPbeta when compared to other AML blasts. This is the first report to describe insertional disruption of the CUGBP1 gene and to suggest a role for the CUGBP1-C/EBPbeta pathway in leukemogenesis.     

逆转录-多重巢式聚合酶链反应技术在急性单核系白血病M4/M5 MLL基因重排检测中的应用

目的 探讨逆转录-多重巢式聚合酶链反应（多重PCR）技术在初诊M4／M5患者MLL基因重排检测中的价值。方法 采用骨髓直接或短期培养法制备染色体，应用R显带技术进行核型分析。采用多重PCR技术，检测40例初诊M4／M5患者中5种急性髓系白血病常见的MLL融合基因以及MLL部分串联重复。结果 R显带揭示7有涉及11q23的易位，包括t（6；11）（q27；q23）、t（9；11）（p21；q23）、t（11；17）（q23；q21）、t（11；19）（q23；p13．1），14例有其他核型异常，19例为正常核型。多重PCR证实了7例核型分析显示11q23易位标本中的6例，例3核型分析揭示46，XX，t（6；11）（q27；q23），多重PCR检测MLL/AF6为阴性；19例显带分析为正常核型标本中检出2例MLL部分串联重复。结论 多重PCR是对初诊M4／M5患者进行各种MLL重排筛检的有效方法。     

Variant translocations (9;11): identification of the critical genetic rearrangement

The t(9;11)(p22;q23) is a recurring abnormality in acute nonlymphocytic leukemia. The analysis of complex 9;11 translocations will aid in the identification of the conserved chromosomal junction or the critical genetic alteration created by the rearrangement; however, variant translocations involving chromosomes #9 and #11 have not been reported. We have identified such variants in two patients who had acute myelomonocytic leukemia and acute monocytic leukemia, characterized by a t(9;11;18)(p22;q23;q12) and a t(9;11;13)(p22;q23;q34), respectively. The conserved junction resulting from these rearrangements is created by the translocation of chromosomal material from 9p to 11q.     

A t(4;11)(q21;p15) in a case of T-cell lymphoma and a case of acute myelogenous leukemia

The translocation (4;11)(q21;p15) has been observed in acute lymphoblastic as well as acute myeloid leukemias (ALL and AML, respectively). We report the first case of T-cell lymphoma with t(4;11)(q21;p15) and a case of AML. The clinical history of and cytogenetics in the latter is suggestive of a secondary leukemia; his karyotype revealed emergence of a t(3;11)(q21;q13) in addition to the t(4;11). Previously reported cases with t(4;11)(q21;p15) are reviewed, clinical and morphological characteristics of cases with t(4;11)(q21;q23) and t(4;11)(q21;p15) are compared, and chromosome abnormalities involving the NUP98 gene in hematologic malignant disorders are reviewed.