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.     

<Emphasis Type="Italic">RABGAP1L</Emphasis> gene rearrangement resulting from a der(Y)t(Y;1)(q12;q25) in acute myeloid leukemia arising in a child with Klinefelter syndrome

In this study, we report the molecular cytogenetic characterization of an acute myeloid leukemia with a der(Y)t(Y;1)(q12;q25) in bone marrow cells in a child with Klinefelter syndrome. Conventional cytogenetics demonstrated the unbalanced translocation, i.e., a trisomic 1q25-qter juxtaposed to Yq12 replaced the terminal segment of chromosome Y was acquired and present only on bone marrow cells. Fluorescence in situ hybridization showed that the breakpoint at 1q25 disrupted RABGAP1L, a strongly expressed gene in CFU-GEMM, erythroid cells, and megakaryocytes, while the Yq12 breakpoint fell within the heterochromatic region. As der(Y)t(Y;1)(q12;q25) was an isolated cytogenetic change, RABGAP1L rearrangement as well as gene(s) dosage effects correlated to 1q25-qter trisomy, and Yq12-qter loss may make a major contribution to leukemogenesis and/or disease progression. Maria Cristina Roberti and Roberta La Starza should be regarded as joint first authors.     

Molecular characterization of complex chromosomal rearrangement: First report of novel t(7;12) (q11;q22) as part of a complex karyotype in de novo AML-M2 case

The strong association of diagnostic karyotype with clinical outcome has made cytogenetics one of the most valuable diagnostic and prognostic tools for acute myeloid leukemia (AML) till today. Complex chromosomal findings are reported to be seen in nearly 10–15% of adult AMLs and are generally associated with poor outcome. In the current report, we present the results of hematologic, immunophenotypic, cytogenetic, chromosomal microarray and molecular analyses of a 60-year-old female patient diagnosed with AML-M2. Cytogenetic analysis revealed complex chromosomal findings involving seven different chromosomes. However, cytogenetic analyses were not able to precisely unveil all karyotypic changes, hence chromosomal microarray was used for further characterization. The most interesting observation was identification of a t(7;12) (q11;q22) as part of this complex karyotype. To the best of our knowledge, this is the first report of identification of novel t(7;12) (q11;q22) as part of a complex karyotype in de novo AML-M2.     

一例伴t(14;14)(q11;q32)易位的B细胞急性淋巴细胞白血病的临床和分子细胞遗传学研究

目的 报告1例伴t(14;14)(q11;q32)易位的罕见B细胞急性淋巴细胞白血病(B-lineage acute lymphoblastie leukemia,B-ALL)病例,阐明其临床和分子细胞遗传学特征.方法 分析1例伴t(14;14)(q11;q32)易位B-ALL患者的临床资料;将患者骨髓细胞24h培养后按常规方法制备染色体标本,采用R显带技术进行核型分析;分别应用IGH双色断裂点分离探针、CEBPE双色断裂点分离探针、4号全染色体涂染探针和ALL组合探针进行荧光原位杂交(fluorescence in situ hybridization,FISH)分析.结果 常规细胞遗传学分析显示患者核型为47,XX,+4,t(14;14)(q11;q32)[20],FISH分析进一步证实了这种核型异常.IGH双色断裂点分离探针FISH分析表明t(14;14)(q11;q32)易位累及IGH基因,CEBPE双色断裂点分离探针FISH分析提示t(14;14)(q11;q32)易位中IGH的伙伴基因为CEBPE基因.结论 在B-ALL中t(14;4)(q11;q32)易位同时累及IGH和CEBPE基因为少见的再现性遗传学异常,该异常可定义B-ALL中一种新的亚型.伴有t(14;14)(q11;q32) IGH/CEBPE易位的B-ALL患者可能预后较好.     

A novel t(11;12)(q23-24;q24) in a case of minimally-differentiated acute myeloid leukemia (AML-M0)

Acute myeloid leukemia with minimal signs of myeloid differentiation (AML-M0) is a recent addition to the FAB group classification. Chromosome data is scarce, but existing reports describe a high incidence of complex karyotypes and myelodysplastic syndrome-like chromosome alterations, while single chromosome translocations have rarely been reported. We describe the case of a 60-year-old woman diagnosed with AML-M0 with a novel translocation t(11;12)(q23-24;q24) as the sole karyotypic marker. Fluorescence in situ hybridization analysis to assess MLL gene splitting did not show rearrangement of this oncogene.     

Pediatric acute myeloid leukemia with t(7;21)(p22;q22)

The t(7;21)(p22;q22) resulting in RUNX1‐USP42 fusion, is a rare but recurrent cytogenetic abnormality associated with acute myeloid leukemia (AML) and myelodysplastic syndromes. The prognostic significance of this translocation has not been well established due to the limited number of patients. Herein, we report three pediatric AML patients with t(7;21)(p22;q22). All three patients presented with pancytopenia or leukopenia at diagnosis, accompanied by abnormal immunophenotypic expression of CD7 and CD56 on leukemic blasts. One patient had t(7;21)(p22;q22) as the sole abnormality, whereas the other two patients had additional numerical and structural aberrations including loss of 5q material. Fluorescence in situ hybridization analysis on interphase cells or sequential examination of metaphases showed the RUNX1 rearrangement and confirmed translocation 7;21. Genomic SNP microarray analysis, performed on DNA extracted from the bone marrow from the patient with isolated t(7;21)(p22;q22), showed a 32.2 Mb copy neutral loss of heterozygosity (cnLOH) within the short arm of chromosome 11. After 2‐4 cycles of chemotherapy, all three patients underwent allogeneic hematopoietic stem cell transplantation (HSCT). One patient died due to complications related to viral reactivation and graft‐versus‐host disease. The other two patients achieved complete remission after HSCT. Our data displayed the accompanying cytogenetic abnormalities including del(5q) and cnLOH of 11p, the frequent pathological features shared with other reported cases, and clinical outcome in pediatric AML patients with t(7;21)(p22;q22). The heterogeneity in AML harboring similar cytogenetic alterations may be attributed to additional uncovered genetic lesions.     

Increased expression of miR-24 is associated with acute myeloid leukemia with t(8;21)

This study was designed to learn the expression status of miR-24 and its clinical relevance in patients with acute myeloid leukemia (AML). We detected the miR-24 expression levels using real-time quantitative PCR in 84 AML patients and investigated the clinical significance of miR-24 expression in AML. There was no difference in clinical parameters between cases with miR-24 high expression and with miR-24 low expression. The frequency of miR-24 high expression was higher in patients with t(8;21) than in others (82% (9/11) versus 44% (32/72), P=0.026). The levels of miR-24 expression had no correlation with the mutations of nine genes (FLT3-ITD, NPM1, C-KIT, IDH1/IDH2, DNMT3A, N/K-RAS and C/EBPA). Meanwhile, among the group who obtained CR, the cases with miR-24 high expression had no difference in overall survival (OS) and relapse-free survival (RFS) than those with miR-24 low expression (P=0.612 and 0.665, respectively). These findings implicated that miR-24 high regulation is a common event in AML with t(8;21), and it might serve as a novel and selective therapeutic target for the treatment of AML with t(8;21).     

混合型急性白血病临床病理探讨并文献复习

目的：探讨混合型急性白血病的临床病理特征、诊断和鉴别诊断、治疗及预后。方法：回顾性分析1例混合型急性白血病患者的临床资料、组织病理形态、免疫组织化学染色、流式细胞学、染色体核型分析、治疗及随访结果,并回顾相关文献。结果：光镜下,颈部淋巴结活检示淋巴结基本结构被破坏,不见明显的淋巴滤泡及套区,代之以小-中等大小的比较均匀一致的异型淋巴样细胞,其细胞质较少,细胞核圆形或卵圆形,染色质比较均匀细腻,核仁不明显或偶见,核分裂象可见。免疫组织化学染色结果显示异型淋巴样细胞LCA散在较多(+),CD7弥漫较多(+),TdT弥漫较多(+),CD10弥漫较多(+),MPO散在(+);外周血涂片和骨髓涂片可见原始幼稚细胞;第一次化疗前后流式细胞学检测分别提示急性髓系白血病和急性B淋巴母细胞白血病。第一次化疗前骨髓短期培养法染色体核型分析提示46、XY、del(11q)。上述淋巴结活检形态学、免疫组织化学染色结果、外周血及骨髓涂片、骨髓流式细胞学及染色体核型分析均支持混合型急性白血病(转换型)的诊断。虽已更换不同的化疗方案,患者化疗效果不明显,反复出现肺部感染及骨髓抑制,均提示其预后比较差。结论：混合型急性白血病十分少见,一般需要结合形态学、免疫表型及细胞遗传学等检查才能做出诊断,对该病的鉴别诊断、治疗方案的选择及预后具有重要意义。     

Chronic myelocytic leukemia with eosinophilia,t(9;12)(q34;p13), and ETV6-ABL gene rearrangement: case report and review of the literature

Chronic myelocytic leukemia (CML) is a chronic myeloproliferative disorder characterized by cytogenetic or molecular evidence of Philadelphia (Ph) chromosome, t(9;22)(q34;q11). Mild to moderate eosinophilia is commonly seen in CML. However, eosinophilia as a dominant feature of CML is extremely rare. We describe a case of Ph(-) CML with eosinophilia. Loeffler endocarditis, and t(9;12)(q34;p13) that resulted in an ETV6-ABL gene rearrangement/fusion identified to the best of our knowledge, for the first time by using commercially available fluorescence in situ hybridization probes.     

FMS hemizygosity in myeloid dysplasia and acute myeloid leukemia with chromosomal aberration del(5)(q) demonstrated by polymerase chain reaction

Interstitial deletions of the long arm of chromosome 5 del(5)(q), are recurring aberrations in the myelodysplastic syndrome and acute myeloid leukemia. Several genes located in region (5)(q23–34) have been implicated as being of pathogenic importance. In this study seven samples of six patients with myelodysplastic syndrome and acute myeloid leukemia who have the del(5)(q) aberration were analyzed by polymerase chain reaction (PCR) and Southern blot technique. FMS hemizygosity was demonstrated in all patients. PCR analysis from peripheral blood samples confirmed the observations of this aberration found by semiquantitative Southern blot. PCR-based analysis can be used for primary diagnosis in addition to cytogenetic evaluation and for follow-up in patients with del(5)(q) aberration.Abbreviations PCR Polymerase chain reaction - MDS Myelodysplastic syndrome - AML Acute myeloid leukemia - RA Refractory anemia - RAEB Refractory anemia with excess of blasts - RAEBt Refractory anemia with excess of blasts in transformation to acute leukemia     

A complex genetic rearrangement in a t(10;14)(q24;q11) associated with T-cell acute lymphoblastic leukemia.

The t(10;14)(q24;q11) is observed in the leukemia cells of 5-10% of cases of T-cell acute lymphoblastic leukemia (T-ALL). Recently, molecular analyses of a number of these translocations revealed simple reciprocal translocations between the T-cell receptor delta chain gene (TCRD) and a region of 10q24. We have characterized, at the molecular level, a t(10;14)(q24;q11) in a patient with T-ALL. The translocation in this case, in contrast to the previous cases, is part of a complex genetic rearrangement. In addition to a reciprocal translocation between the D delta 3 gene segment of TCRD and a region of 10q24, a local inversion occurred within TCRD, involving the D delta 2 and V delta 2 gene segments. As a consequence, the entire joining and constant regions and most of the diversity regions of TCRD are located on the derivative 14 chromosome, whereas the joining and constant regions of TCRA are positioned on the derivative 10 chromosome. The chromosome 10 breakpoint in our patient, as in other t(10;14), clusters within a 9 kb breakpoint region. The occurrence of seven breakpoints within a localized region of chromosome 10 implies the existence of a nearby gene whose activation may have conferred a selective advantage on the leukemia cells. Moreover, as in the previous cases, the translocation in the present study exhibits recombination signal sequences or signal-like sequences adjacent to the breakpoint junction. The presence of such motifs suggests the involvement of the recombinase enzyme system in the generation of this genetic alteration.     

Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: Data from Nordic Society for Pediatric Hematology and Oncology (NOPHO‐AML) and review of the literature

The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO‐AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3‐year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3‐year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.     

Burkitt t(8;14)(q24;q32) and cryptic deletion in a CLL patient: report of a case and review of literature

A 53-year-old man diagnosed with chronic lymphocytic leukemia (CLL)-small lymphoma following splenectomy was found to have a t(8;14) with an apparent cryptic deletion of the MYC gene. This patient's spleen and bone marrow (BM) showed that 93% and approximately 70% of the viable cells, respectively, were lambda-monoclonal B-cells coexpressing CD5 with CD20, CD19, CD23, CD22, CD38, and low FMC-7. The smear showed a marked increase in small, mature lymphoid cells, with <2% prolymphocytes. The BM karyotype was 46,XY,t(8;14)(q24;q32),-18,+mar[3]/46,XY[27] and FISH analysis with an IGH/MYC green-red dual-fusion signal probe showed an atypical interphase result of one fusion, two green, and one red signal in 70% of the cells. The MYC dual red-green split-apart probe showed the expected t(8;14) pattern in 62% of the cells; however, sequential FISH on a t(8;14) GTG-metaphase showed the single fusion signal on derivative chromosome 8 and only a green signal on der(14) for the IGH/MYC dual-fusion probe and a green signal on der(14), red signal on der(8), and fusion signal on the normal chromosome 8 for the MYC split-apart probe. Thus, the apparently balanced t(8;14) had a cryptic deletion (approximately 1.6 Mb) between the red and the green regions flanking the MYC gene in the MYC split-apart probe, 128,585,631-130,226,339 bp from 8pter. The rarity of t(8;14) in CLL together with a cryptic deletion that probably includes the MYC gene in our CLL patient persuaded us to explore the clinicopathological role of MYC translocations by comparing disease progression in our patient and in other reported CLL cases.     

Tetraploidy acute promyelocytic leuemia with double t(15;17)/PML-RARA,a case report with review of literature

Acute promyelocytic leukemia (APL) with tetraploidy chromosome harboring t(15;17)(q23;a21) is extremely rare. To date, there are 14 such cases reports that describe this entity, mostly found in Eastern hemisphere. Herein we described a 51-year-old man with a diagnosis of tetraploid acute promyelocytic leukemia with double (15;17) translocations and compare the prototypically clinicopathologic, genetic and molecular findings with those reported in the literature.     

Acute promyelocytic leukemia with cryptic t(15;17) on isochromosome 17: a case report and review of literature

Acute Promyelocytic Leukemia (APL) is one of the most curable leukemia which shows great sensitivity to all-trans retinoic acid (ATRA) although a small number of the patients present poor prognosis and short survival. Isochromosome 17 in APL which usually bears an additional copy of RARA/PML fusion gene is considered to be a negative factor on its prognosis. Cryptic t(15;17) on i(17q) leads to an extra copy of PML/RARA rather than RARA/PML which may confer a worse prognosis. We describe here a rare APL case with complex chromosomal abnormality including isochromosome 17 bearing cryptic t(15;17) showing poor outcome. The patient lacks a classic t(15;17) and fluorescence in situ hybridization (FISH) presents 2 PML/RARA fusion signals on both long arms of the isochromosome. The patient also acquired a secondary mutation at relapse when the initial karyotype was already a complex karyotype involving chromosome 13, 17 and 22 at the same time. The poor response of this patient to traditional chemotherapy like ATRA and novel therapy like arsenic trioxide (ATO) suggests that early auto-hematological stem cell transplantation may be the choice of APL with isochromosome 17 especially with cryptic t(15;17) on i(17q). We are the first to show a clear history and evidence of FISH of these kind of cases. A small summary of cases with cryptic t(15;17) on isochromosome 17 is also made.     

Chronic myeloid leukemia with variation of translocation at (Ph) [ins (22;9) (q11;q21q34)]: a case report

Chronic myeloid leukemia (CML) is most frequently observed in middle-aged individuals. In most patients, normal marrow cells are replaced by cells with an abnormal G-group chromosome, the Philadelphia (Ph) chromosome. The Ph chromosome that is characterized by the translocation (9;22) (q34;q11) is noted in 90-95% of patients diagnosed with CML. Studies have also shown that CML can be associated with various other cytogenetic abnormalities, with 5-10% of these cases showing complex translocation involving another chromosome in addition to the Ph chromosome. Here, we report the case of a Ph(+) CML patient with an inserted karyotype who presented clinically in the chronic phase but with atypical features. This case highlights the significance of cytogenetic abnormalities on the prognosis in CML.     

Isochromosome (17)(q10) and translocation (4;12)(q12;p13) in a child with acute myeloid leukemia.

Isochromosome 17q is a commonly observed cytogenetic aberration in hematologic malignancies. Isolated isochromosome 17q usually presents as a marker of a chronic myeloid disorder, with a high propensity for transformation into acute nonlymphoblastic leukemia (ANLL). t(4;12)(q11-12;p13) is a recently described translocation, associated with ANLL, predominantly in adults. In this article, we present a case of acute myeloblastic leukemia (AML) in a 14-year-old female in which i(17q) and t(4;12)(q12;p13) were found in the leukemic clone at diagnosis. We briefly review the literature and hypothesize as to the significance of the coexistence of these cytogenetic changes.