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.     

Translocation (11;16)(q23;p13) acute myelogenous leukemia and myelodysplastic syndrome

The purpose of this study is to examine the relationship of t(11;16)(q23;p13) to the type of myeloproliferative disorder noted by hematopathology. Previously, t(11;16) has been reported in fewer than 20 patients, all with the diagnosis of therapy-related (secondary) acute myelogenous leukemia (sAML) or myelodysplastic syndrome (MDS). Putative involved genes are the MLL on 11q23 and CBP at 16p13. Data from The University of Texas M. D. Anderson Cancer Center (UTMDACC) Cytogenetics Laboratory revealed 3 patients with t(11;16) observed during the past 5 years. Two of the patients had a prior diagnosis of non-Hodgkin lymphoma (NHL) and had been treated with chemotherapy, which included cyclophosphamide. The other patient presented with de novo AML and no history of cancer or chemotherapy. Two of the 3 patients had t(11;16) as the sole cytogenetic abnormality. One patient had a t(11;16) clone that included t(9;21) and t(10;21) as additional changes. Translocation (11;16) has previously been reported only as being therapy-related. In this study, the t(11;16) was seen in 2 patients with previous lymphomas treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). A single patient with apparently de novo AML constitutes the first reported instance of non-treatment associated t(11;16) AML.     

Translocation (1;11)(q23;p15), a novel simple variant of translocation (7;11)(p15;p15), in a patient with AML (M2) accompanied by non-Hodgkin lymphoma and gastric cancer

We describe a case of an acute myelogenous leukemia (AML) associated with t(1;11) (q23;p15), which is a novel simple variant translocation of t(7;11)(p15;p15). The patient was a Japanese man who had a history of non-Hodgkin lymphoma (NHL) and received MACOP-B combination chemotherapy. Fifteen months after the completion of the treatment, the patient developed AML (M2), which was regarded as a therapy-related leukemia. Cytogenetic study of bone marrow cells showed t(1;11). Although he achieved complete remission by combination chemotherapy, a relapse of NHL and gastric cancer were revealed in the course of the consolidation chemotherapy for AML. The NHL was considered a histological conversion from follicular lymphoma because lymphoma cells carried t(14;18) (q32;q21) and were strongly positive for BCL2 protein. Translocation (1;11), together with AML having t(7;11) or inv(11) involving 11p15, shows that 11p15 is a common acceptor site of these chromosome aberrations and suggests the significance of the NUP98 gene located in 11p15 in therapy-related leukemia.     

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).     

A novel chromosomal rearrangement associated with therapy-related acute leukemia

We describe a 7-year-old girl with therapy-related acute myeloid leukemia (AML) associated with a single and novel karyotypic abnormality. The patient had been treated with alkylating agents and etoposide for hypothalamic pilocytic astrocytoma at age 17 months, and developed mixed lineage AML. Cytogenetic analysis of the leukemic blasts showed 46,XX,der(7)t(7;11)(q22;q14) in all cells examined. Southern blot analysis revealed three copies of an unrearranged MLL gene on chromosome 11q. This is the first report of a triplicated, unrearranged MLL gene in association with a deletion of 7q anomaly and an unbalanced translocation in therapy-related leukemia.     

Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop

Seventy-seven patients were identified with Rare recurring (excluding 11q23, 21q22, inv(16), and t(15;17)) chromosome abnormalities among 511 patients with treatment-related myelodysplastic syndromes and acute leukemia accepted from centers in the United States, Europe, and Japan. The abnormality subsets included 3q21q26 (17 patients), 11p15 (17 patients), t(9;22)(q34;q11) (10 patients), 12p13 (9 patients), t(8;16)(p11;p13) (9 patients), and an "other" subset, which included t(6;9)(p23;q34) (3 patients), t(10;11)(p13;q13 approximately q21) (3 patients), t(1;17)(p36;q21) (2 patients), t(8;14)(q24;q32) (2 patients), t(11;19)(q13;q13) (2 patients), t(1;3)(p36;q21) (2 patients), and t(3;5)(q21;q31) (1 patient). Increased karyotypic complexity with additional balanced and unbalanced rearrangements was observed in 70% of cases. Among 54 cases with secondary abnormalities, chromosome 5 and/or 7 abnormalities were observed in 59%. The most frequent primary diseases were breast cancer (24 cases), Hodgkin disease (14 cases), non-Hodgkin lymphoma (10 cases), and de novo ALL (5 cases). Thirty-seven patients received alkylating agents plus topoisomerase II inhibitors with or without radiation therapy. The presenting diagnosis was t-AML in 47 cases, t-MDS in 23 cases (10 progressed to t-AML), and t-ALL in seven cases, five of whom had a t(9;22). The median latency time from initiation of original therapy to therapy-related disease diagnosis was quite long (69 months), and the overall median survival from the date of therapy-related disease diagnosis was very short (7 months). The 1-year survival rate was 34 +/- 7%, with no significant differences among subsets. Comparison with previously reported cases showed increased karyotypic complexity and adult presentation of pediatric-associated chromosome abnormalities.     

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.     

New complex t(2;11;17)(p21;q23;q11), a variant form of t(2;11), associated with del(5)(q23q32) in myelodysplastic syndrome-derived acute myeloblastic leukemia

The t(2;11)(p21;q23) is a rare recurrent aberration observed in myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). It has been suggested that t(2;11) is specifically associated with a deletion of the long arm of chromosome 5 (5q). A 63-year-old man was initially diagnosed as AML with del(5)(q23q32) as a sole abnormality. At relapse, t(2;11;17)(p21;q23;q11) in association with del(5q) appeared in 14 of 20 cells by G-banding. Spectral karyotyping confirmed three derivative chromosomes, der(11)t(2;11), der(17)t(11;17), and der(2)t(2;17). Fluorescence in situ hybridization analysis with a probe for MLL demonstrated that the breakpoint at 11q23 was telomeric to the MLL gene. Nine of 10 reported cases with t(2;11) and del(5q) had MDS including 5q- syndrome and four of them evolved to AML, as observed in the present case. Our results indicated that t(2;11;17) was a secondary genetic change, which appeared during disease progression after del(5q) was observed. Furthermore, considering another reported case, the MLL gene seems to be not involved in the pathogenesis of MDS/AML with t(2;11) and del(5q).     

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。     

Granulocytic sarcomas in body cavities in childhood acute myeloid leukemias with 11q23/MLL rearrangements

Three childhood acute monoblastic leukemias (AML M5) with granulocytic sarcomas (GSs) are described. All displayed 11q23/MLL abnormalities, t(9;11)(p22;q23) in two cases and t(11;17)(q23;q21) in one case, constituting around 20% of all 11q23-positive AML cytogenetically investigated in our department. Two of the patients had GS in multiple locations, and all three had abdominal GS. In two of them, t(9;11)-positive GS was diagnosed prior to the diagnosis of AML. Fourteen (1.9%) of 752 published AML cases with 11q23 aberrations have had GS, either as a presenting feature or during disease progression. The incidence of GS has varied significantly (P < 0.05) between children (3.8%) and adults (0.8%). The most common AML subtype has been AML M5 ( approximately 75%) and the most frequent GS sites have been the skin, abdomen, orbit, and thorax. Considering the possibility of underreporting of GS in published cases and the relatively high frequency in our own series, we believe that 11q23/MLL rearrangements may predispose to GS development. Although extramedullary infiltrates in the skin are known to be frequent in cases of AML M5, which is often associated with 11q23 aberrations, the present findings indicate that GS in the abdomen, orbit, and thorax may also be common, especially in pediatric AML. Thus, the possibility of 11q23/MLL-positive GS should be suspected when tumors of uncertain derivation occur in these sites. Finally, the identification of 11q23/MLL abnormalities in GSs in two patients without overt AML underscores the importance of using cytogenetic and molecular genetic investigations as a diagnostic approach in the evaluation of tumorous lesions of unknown origin. Genes Chromosomes Cancer 27:136-142, 2000.     

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.     

Quantitative acute leukemia cytogenetics.

Using literature data on cytogenetic abnormalities in 3,612 cases of acute myeloid leukemia (AML) and 1,551-cases of acute lymphocytic leukemia (ALL), we have attempted to quantify the information value of finding the typical ALL- and AML-associated chromosome aberrations. Sensitivity, specificity, and predictive value of finding or not finding a given aberration were calculated for several diagnostic scenarios: for the differential diagnosis between ALL and AML when the patient is known to have acute leukemia, for the differential diagnosis among AML FAB subtypes in a patient with known AML, and for the differential diagnosis between ALL FAB subtypes in a patient with known ALL. The specificities were generally high, close to 1. The highest sensitivities in AML were found for +8, t(15;17)(q22;q11), t(8;21)(q22;q22), and -7 (all greater than 0.1), and in ALL for t(9;22)(q34;q11), t(4;11)(q21;q23), and +21 (again all greater than 0.1). In the AML subtypes, the highest sensitivities were 0.89 for t(15;17)(q22;q11) in M3, followed by 0.40 for t(8;21)(q22;q22) in M2, 0.30 for inv(16)(p13q22)/del(16)(q22)/t(16;16)(p13;q22) in M4, and 0.16 for t(9;11)(p21;q23) in M5. In the ALL subtypes, the highest sensitivities were 0.71 and 0.11 for t(8;14)(q24;q32) and t(8;22)(q24;q11), respectively, in L3, 0.23 for t(9;22)(q34;q11) in L2, and 0.18 and 0.13 for +21 and t(4;11)(q21;q23), respectively, in L1. The highest (1.0) positive predictive values in the AML versus ALL comparison were found for t(1;3)(p36;q21), inv(3)(q21q26), t(6;9)(p23;q34), t(7;11)(p15;p15), t(8;16)(p11;p13), t(8;21)(q22;q22), t(15;17)(q22;q11), and, as sole anomalies, for +4, +9, and +11. In the reverse comparison, ALL versus AML, positive predictive values of 1.0 were found for t(1;14)(p32-34;q11), dup(I)(q12-21q31-32), t(2;8)(p12;q24), t(8;14)(q24;q32), t/dic(9;12)(p11-12;p11-13), t(10;14)(q24;q11), and t(11;14)(p13;q11). Among the AML subgroups, the highest predictive values were: 1.0 for M3 if t(15;17), 0.91 for M2 if t(8;21), 0.86 for M4 if inv/del(16)/t(16;16), and 0.82 for M5 if t(9;11). Among the ALL subtypes, positive predictive values of greater than 0.8 were reached only for the L3-associated aberrations t(2;8) (1.0), t(8;14) (0.95), t(8;22) (0.87), and dup(I) (0.80). The highest negative predictive values were in AML 0.98 that the disease is not M3 if t(15;17) is not found, and in ALL 0.96 that the patient does not have L3 if a t(8;14) is not detected.     

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.     

Therapy-related acute leukemia with mixed phenotype and t(9;22)(q32;q11.2): a case report and review of the literature

Therapy-related acute leukemia showing mixed phenotype is extremely rare. We report a 49-year-old woman who presented with palpable masses in her neck and back. She had received systemic chemotherapy (adriamycin and cisplatin) and radiotherapy for endometrial adenocarcinoma 7 years before. Her peripheral blood and bone marrow showed increased blasts, which coexpressed myeloid (CD13, CD33, and myeloperoxidase) and B-lymphoid antigens (CD19 and CD79a). Cytogenetic analysis showed a karyotype of 46,XX,dup(1)(q21q32),add(5)(q33),t(9;22)(q34;q11.2)[12]/47,idem,+der(22)t(9;22)[8], and BCR/ABL1 rearrangement was detected. Leukemic infiltration was also confirmed in her back mass. After induction chemotherapy with idarubicin, cytarabine, and imatinib, she achieved complete remission. Only 2 cases of therapy-related acute leukemia with mixed phenotype have been reported so far: one with hyperploidy and the other with t(1;21)(p36;q22). To the best of our knowledge, this is the first case of therapy-related acute leukemia with mixed phenotype and t(9;22) as well as extramedullary leukemic infiltrations.