An unusual three-way translocation t(21;8;1)(q22;q22;q32) in a case of acute myeloid leukemia (M2)

Variant forms of the classic translocation t(8;21) are uncommon and account approximately 3% of all t(8;21)(q22;q22) in acute myeloid leukemia (AML) patients. These forms involve chromosomes 8, 21, and other chromosomes. Here we report a Tunisian patient with a complex rearrangement t(21;8;1)(q22;q22;q32) revealed by conventional chromosomal study at diagnosis. Fluorescence in situ hybridization study revealed the presence of the AML1-ETO chimeric gene on the derivative chromosome 8. To the best of our knowledge, this is the second case of t(21;8;1) of AML-M2 reported in the literature with the involvement of the same breakpoint at 1q32. This illustrates that this complex translocation is rarely encountered in AML and reinforces the fact that this region may harbour a critical gene candidate that may play an important role in the pathogenesis of AML. More cases are needed to elucidate its clinical features and prognosis.     

Molecular characterization of AML with ins(21;8)(q22;q22q22) reveals similarity to t(8;21) AML

In acute myeloid leukemia (AML), nonrandom clonal chromosome aberrations are detectable in ～ 55% of adult cases. Translocation t(8;21)(q22;q22) resulting in the 5'RUNX1/3'RUNX1T1 fusion gene occurs in ～ 8% of AML cases. Also, ins(8;21) and ins(21;8) have been described that show a broad heterogeneity at the molecular level with inserted fragment sizes ranging from 2.4 to 44 Mb. Microarray-based comparative genomic hybridization (arrayCGH) in 49 intermediate-risk AML and RT-PCR-based screening in 532 AML cases allowed the detection of ins(21;8)/ins(8;21) in three cases; arrayCGH and subsequent RT-PCR revealed an ～ 0.5 Mb sized inserted fragment generating the 5'RUNX1/3'RUNX1T1 fusion gene in one case with a submicroscopic ins(21;8)(q22;q22q22) whereas the other two cases were identified by banding analysis and RT-PCR, respectively. Gene expression profiling (GEP) and a detailed review of the literature highlighted similar biological features of AML cases with ins(21;8)/ins(8;21) and t(8;21)(q22;q22). Our study demonstrates the potential of high-resolution array-based analysis and GEP and provides further evidence that AML with insertions generating the 5'RUNX1/3'RUNX1T1 fusion not only biologically resemble the t(8;21)(q22;q22) AML subgroup, but might also share its prognostically favorable clinical behavior. Thus, similar treatment options should be considered in these patients.     

Molecular cytogenetic investigations in a novel complex variant of t(8;21)(q22;q22) with ins(15;21)(q15;q22.2q22.3) in a patient with AML-M2 subtype

Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease characterized by the aberrant proliferation of myeloid stem cells, reduced apoptosis and blockage in cellular differentiation. The present report describes the results of hematological, cytogenetic, and fluorescence in situ hybridization (FISH) analysis in a 25-year-old man diagnosed with AML-M2. Cytogenetic as well as FISH analysis revealed a complex translocation involving four chromosomes, with the karyotype 45,−Y,der(X)t(X;8)(p21;q22),der(8)t(8;21)(q22;q22),ins(15;21)(q15;q22.2q22.3),der(21)t(8;21)(q22;q22). The breakpoints at 8q22 and 21q22 suggested a rearrangement of the RUNX1T1 (alias ETO) and RUNX1 (previously AML1) genes, respectively. Using a dual-color FISH test with RUNX1T1 and RUNX1 probes, we demonstrated an RUNX1/RUNX1T1 fusion signal on the derivative chromosome 8, establishing this translocation as a novel complex variant of t(8;21)(q22;q22).     

Targeting of AML1-ETO in t(8;21) leukemia by oridonin generates a tumor suppressor-like protein

Nearly 60% of acute myeloid leukemia (AML) patients with the t(8;21)(q22;q22) translocation fail to achieve long-term disease-free survival. Our previous studies demonstrated that oridonin selectively induces apoptosis of t(8;21) leukemia cells and causes cleavage of AML1-ETO oncoprotein resulting from t(8;21), but the underlying mechanisms remain unclear. We show that oridonin interacted with glutathione and thioredoxin/thioredoxin reductase to increase intracellular reactive oxygen species, which in turn activated caspase-3 in t(8;21) cells. Moreover, oridonin bound AML1-ETO, directing the enzymatic cleavage at aspartic acid 188 via caspase-3 to generate a truncated AML1-ETO (ΔAML1-ETO) and preventing the protein from further proteolysis. ΔAML1-ETO interacted with AML1-ETO and interfered with the trans-regulatory functions of remaining AML1-ETO oncoprotein, thus acting as a tumor suppressor that mediates the anti-leukemia effect of oridonin. Furthermore, oridonin inhibited the activity of c-Kit(+) leukemia-initiating cells. Therefore, oridonin is a potential lead compound for molecular target-based therapy of leukemia.     

Acute myeloid leukemia (AML) with t(8;21)(q22;q22) relapsing as AML with t(3;21)(q26;q22)

We here report on an 48-year-old male patient with a primary diagnosis of acute myeloid leukemia (AML)-M2 with t(8;21)(q22;q22), who developed complete hematologic and molecular remission after induction chemotherapy. Thirteen months later, he relapsed and showed an AML-M2 with t(3;21)(q26;q22). Retrospectively, polymerase chain reaction (PCR) for AML1-EVI1 and EVI1 overexpression was performed on bone marrow and peripheral blood samples taken at diagnosis and during the first year after the first manifestation of AML to quantify the AML1-EVI1-positive clone. In a bone marrow sample taken 25 days from diagnosis, PCR for AML1-EVI1 was negative, and EVI1 expression, as assessed by quantitative real-time PCR, was within the same range as that of healthy controls. These data suggest that this patient developed a secondary therapy-related AML rather than a relapse.     

Detection of a t(8;21)(q22;q22) in a Case of M5 Acute Monoblastic Leukemia

Although the translocation (8;21) is the single most common structural rearrangement reported in acute myeloblastic leukemia (AML), it is rarely seen in AML FAB type M5. We describe a case of a 51-year-old male with a diagnosis of acute monoblastic leukemia (AML M5b with hemophagocytic component) whose karyotype showed at (8;21)(q22;22). To our knowledge, this is the first report of this translocation in an AML M5b. The t(8;21) has been associated with a good prognosis, but our patient suffered a fast and fatal evolution.     

t(8;21)急性髓细胞白血病发病机制的研究进展

t(8;21)(q22,q22)是急性髓细胞白血病最常见的染色体易位，易位形成的AML1/ETO融合基因在白血病中起重要作用。AML1/ETO可抑制AML1靶基因的活化，也可通过多种途径影响多种转录因子，干扰细胞正常的增殖与分化而致细胞转化。     

Two cases of acute myeloblastic leukemia (M2 type) with karyotypes 45X,-X,t(6;8)(q27;q22),inv(9) and 46,XY,t(8;21)(q22;q22),del(9)(q22)

Two patients with acute myelogenous leukemia (AML) are described. The first case is that of a patient with AML who had a low leukocyte alkaline phosphatase level associated with a variant (6;8)(q27;q22) translocation, coupled with loss of an X chromosome in bone marrow and unstimulated blood cells. The second case is that of an AML patient in whom the karyotype of the leukemic cells at the time of diagnosis was 46,XY,t(8;21)(q22;q22),del(9)(q22); at relapse, the patient acquired an additional chromosome #19. The lack of involvement of chromosome #21 in the first case, as well as the occurrence of an abnormality of chromosome #9, in addition to the t(8q-;21q+) in the second case are discussed with reference to the character of the possible specific chromosomal events in patients with type M2 AML.     

t(8;21)(q22;q22) in blast phase of chronic myelogenous leukemia

The blast phase of chronic myelogenous leukemia (CML) frequently is associated with cytogenetic evidence of clonal evolution, defined as chromosomal aberrations in addition to the t(9;22)(q34;q11.2). We identified the t(8;21)(q22;q22) and other cytogenetic abnormalities by conventional cytogenetics and fluorescence in situ hybridization in 2 patients with t(9;22)-positive CML at the time of blast phase. The t(8;21), which typically is associated with a distinct subtype of de novo acute myeloid leukemia (AML) carrying the aml1/eto fusion gene, was accompanied by increased bone marrow myeloblasts (33%) in case 1 and extramedullary myeloid sarcoma in case 2, suggesting its possible role in disease progression. In case 1, the leukemic cells in aspirate smears had salmon-colored cytoplasmic granules, and immunophenotypic studies showed that the blasts expressed CD19. These findings suggest that the pathologic features of blast phase CML with the t(8;21) resemble those of de novo AML with the t(8;21).     

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.     

Duplication 15q in a patient with t(8;21) acute myeloblastic leukemia (M2)

We present unique chromosomal abnormalities found in a patient with acute myeloblastic leukemia (AML) of French-American-British subtype M2. The patient was referred for an evaluation of chromosomal anomaly associated with AML. She was found to have an abnormal karyotype 46,XX,t(8;21)(q22;q22), and a questionable dup(15)(q15q22) in the majority of cells analyzed. Two cells had the same chromosomal anomalies plus a duplicated derivative chromosome 21 [der(21)t(8;21)(q22;q22)]. These cytogenetic findings were confirmed by fluorescence in situ hybridization utilizing the appropriate DNA probes. To our knowledge, this is the first case report of a combination of the translocation between chromosomes 8 and 21, a duplication of chromosome 15 [dup(15)(q15q22), and a duplicated derivative chromosome 21 [der(21)t(8;21)(q22;q22)].     

Homozygosity for 8pter----q22 in acute myeloblastic leukemia with t(8;21)(q22;q22)

A case of acute nonlymphocytic leukemia with homozygosity for the chromosome segment 8pter----8q22 is reported. A t(8;21)(q22;q22) translocation was associated with duplication of the derivative chromosome 8q- and absence of the normal chromosome 8. These rearrangements also yielded hemizygosity for 8q22----qter. This case shows that acquired hemizygosity and homozygosity do exist in leukemia as in solid malignant tumors.