Translocation (11;19)(q23;p13.3) associated with a novel t(5;16) (q13;q22) in a patient with acute myelocytic leukemia

A novel association of t(11;19)(q23;p13) and t(5;16)(q13;q22) was detected by G-banding and spectral karyotyping studies in an 18-year-old patient. While balanced t(11;19) has been often described in acute myelocytic leukemia (AML) French-American-British Cooperative Group subtypes M4 and M5, this patient was diagnosed with the variant AML-M4 with eosinophilia (AML-M4Eo), which is associated with abnormalities in 16q22 and has good prognosis. However, the patient relapsed after allogeneic transplant and died within 2 years of diagnosis, which suggests that the association of these two translocations correlates with a poor prognosis. This report expands the molecular basis of the variability in clinical outcomes and adds the novel t(5;16)(q13;q22) to the spectrum of chromosome 16q22 abnormalities in AML.     

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.     

Translocation (8;18;16)(p11;q21;p13). A new variant of t(8;16)(p11;p13) in acute monoblastic leukemia: case report and review of the literature

A complex three-way t(8;18;16)(p11;q21;p13) was detected in a 15-month-old patient with acute myeloid leukemia (AML). The patient had typical clinical manifestation and bone marrow features of AML subtype M5b associated with t(8;16)(p11;p13). Therefore, we believe that the t(8;18;16) is a new variant of t(8;16) related to AML M4/M5. We also review other t(8;16)(p11;p13) variants reported in the literature.     

Gain of multiple copies of the CBFB gene: a new genetic aberration in a case of granulocytic sarcoma

Granulocytic sarcomas (GS) are tumor masses of immature myeloid cells presenting at an extramedullary site, mainly the skin, bone, and lymph node. They are often associated with acute myeloid leukemia (AML) with monoblastic or myelomonocytic differentiation, including either AML M2 with t(8;21)(q22;q22) or AML M4Eo with inv(16)(p13q22). We present a case diagnosed with GS associated with AML M4 that presented a normal karyotype with conventional cytogenetic analysis. Although the myeloblasts did not show the inv(16)(p13q22) (CBFB/MYH11), a gain of multiple copies of the CBFB gene was detected with fluorescence in situ hybridization analysis. To our knowledge, no cases with this rare genetic anomaly have been previously described.     

A unique structural abnormality of chromosome 16 resulting in a CBF beta-MYH11 fusion transcript in a patient with acute myeloid leukemia, FAB M4

A 43-year-old female with a peripheral white cell count of 118.0 x 10(9)/L and 96% blasts was diagnosed with acute myeloid leukemia (AML), FAB M4. Cytogenetics, performed on a bone marrow sample, revealed the following abnormal karyotype: 46,XX,ins(16)(q22p13.1p13. 3). Fluorescence in situ hybridization (FISH) confirmed the inter-arm insertion using a probe for 16p. The result of this structural rearrangement was the fusion of CBF beta to MYH11 seen commonly in inv(16)(p13q22). The patient commenced high-dose intensive combination chemotherapy (big ICE; Idarubicin, Cytarabine, and Etopiside). Five days post chemotherapy, she developed febrile neutropenia. Despite broad spectrum intravenous antibiotics and antifungal therapy, the patient died at day nine post chemotherapy. This case demonstrates a previously unreported structural abnormality of chromosome 16 in a patient with AML M4, which represents a third mechanism to inv(16)(p13q22) and t(16;16)(p13q22) in producing the CBF beta-MYH11 fusion. CBF beta-MYH11 fusions masked by cryptic translocations at the cytogenetic level have been detected by FISH and PCR techniques. Due to the improved prognosis associated with CBF beta-MYH11 fusions compared to the standard risk group for AML, its detection remains important.     

Deletion of CBFB in a patient with acute myelomonocytic leukemia (AML M4Eo) and inversion 16

Acute myelomonocytic leukemia with bone marrow eosinophilia (AML M4Eo) is a subtype of AML with distinct morphological features. Inversion (16)(p13.1q22), t(16;16)(p13.1;q22), and del(16)(q22) are nonrandom abnormalities associated with AML M4Eo and a favorable prognosis, compared with the standard risk group for AML. Deletions of the proximal region of the MYH11 gene located at 16p13.1 have been detected in about 20% of patients with inv(16), with an undetermined effect on patient survival. We present the case of a patient with AML M4Eo and inversion 16 with a distal deletion of the CBFB gene at 16q22 detected with fluorescence in situ hybridization. To our knowledge, only one previous report of a similar deletion has appeared in the literature.     

inv(16)(p13q22) in chronic myelogenous leukemia in blast phase: a clinicopathologic, cytogenetic, and molecular study of five cases

Blast phase (BP) in chronic myelogenous leukemia (CML) frequently is accompanied by cytogenetic abnormalities in addition to t(9;22)(q34;q11.2). We describe 5 patients with CML in blast phase (CML-BP) in which t(9;22) and inv(16)(p13q22) were identified by conventional cytogenetics, with confirmation of BCR-ABL and CBFss-MYH11 by fluorescence in situ hybridization. The morphologic findings at the time of BP resembled de novo acute myeloid leukemia (AML) carrying inv(16)(p13q22), with abnormal eosinophils in the bone marrow and monocytosis in the peripheral blood in all cases. In 1 patient, inv(16)(p13q22) and abnormal eosinophils were detected in the bone marrow 2 months before CML-BP. The clinical course of these patients was similar to patients with CML-BP without evidence of inv(16)(p13q22). These cases illustrate that inv(16)(p13q22) is a form of cytogenetic evolution that rarely occurs in patients with CML at the time of BP. In this setting, unlike de novo AML, inv(16)(p13q22) in CML-BP is not associated with a favorable prognosis.     

Inversion of chromosome 16 with the Philadelphia chromosome in acute myelomonocytic leukemia with eosinophilia. Report of two cases.

Two cases are described with the rare combination of inv(16)(p13q22), strongly associated with acute myelomonocytic leukemia with eosinophilia, M4Eo, and the Philadelphia translocation, t(9;22)(q34;q11), hallmark of chronic myeloid leukemia (CML) and rarely found, (less than 1%), in acute nonlymphocytic leukemia. The patients were: case 1, a 9-year-old girl presenting with a white blood cell count (WBC) 42 x 10(9)/L with 32% blasts and bone marrow with blasts and eosinophil precursors consistent with M4Eo, and case 2, a 25-year-old man with WBC 34.7 x 10(9)/L with 13% blasts and bone marrow with features of M4Eo and basophilia. Both patients achieved remission but died following bone marrow transplantation in first remission (case 1) or in relapse (case 2). Cytogenetic findings were: case 1, at diagnosis, 46,XX,inv(16)(p13q22)(21)/46,XX,t(9;22) (q34;q11),inv(16)(8)/46,XX(10), and case 2, at diagnosis, 46,XY,t(9;22) (q34;q11),inv(16)(p13q22) (16) and in remission, 46,XY,t(9;22)(q34;q11) (1)/46,XY (24). Investigation of the breakpoint on 22 in case 1 with Southern blotting and the polymerase chain reaction demonstrated the presence of a p190 mRNA and a breakpoint typical of acute leukemia. Thus a diagnosis of M4Eo was supported by clinical and cytogenetic sequelae in each case; the Ph in case 1 was apparently secondary to inv(16), in case 2 the Ph probably preceded inv(16) in the etiology of the leukemia.     

Deletion of 16q11 is a recurrent cytogenetic aberration in acute myeloblastic leukemia during disease progression.

Abnormalities of chromosome 16 other than inv(16)(p13q22), t(16;16)(p13;q22), and del(16)(q22) have not been fully characterized in acute myeloblastic leukemia (AML) and myelodysplastic syndrome (MDS). We report here the first case of AML with del(16)(q11) as a sole abnormality. A 53-year-old woman was initially diagnosed as MDS, refractory anemia with excess of blasts in transformation with normal karyotype. After sixteen months, the disease progressed to overt AML-M1. Myeloblasts were positive for CD13, CD33, and CD34, but negative for HLA-DR. Chromosome analyses of the bone marrow cells showed 46,XX,del(16)(q11) in all metaphase spreads. Multicolor spectral karyotyping also confirmed that del(16)(q11) was not derived from a cryptic translocation, but a simple deletion. Our results, together with three previously reported cases, suggest that del(16)(q11) may be one of the recurrent aberrations in AML and that it could be associated with clonal evolution or disease progression.     

Cohabiting t(12;22) and inv(3) primary rearrangements in an acute myelomonocytic leukemia (FAB M4) cell line

We describe the cytogenetic characterization of MUTZ-3, the first continuous cell line to be established from acute myelomonocytic leukemia (FAB M4) cells, exhibiting recurrent chromosomal rearrangements associated with this disease category. MUTZ-3 was established from peripheral blood taken at presentation from a 29-year-old male patient and carries the t(12;22)(p13.2;q11.2) associated with acute myelomonocytic leukemia (AMMoL), the inv(3)(q21.2q26.3) associated with multilineage acute myeloid leukemias (AML), and the inv(7)(p14q35) associated with ataxia telangiectasia (A-T). There was no evidence that the patient was an A-T heterozygote. The breakpoint on chromosome 22 mapped between 5'BCR and D22S39, consistent with the G-banding assignment. Both inversions were translocation-associated and may be further examples of an association previously described in AML FAB M4eo with inv(16). We suggest that the combination of inv(3)/t(3;3) with t(12;22) may represent a new, nonrandom association in AML. Genes Chromosom Cancer 16:144–148 (1996). © 1996 Wiley-Liss, Inc.     

Acute monocytic leukemia with (8;22)(p11;q13) translocation Involvement of 8p11 as in classical t(8;16)(p11;p13)

A new case of acute monocytic leukemia observed in a 73-year-old male (ANLLM5) with an unusual t(8;22)(p11;q13) is reported. The blasts did not demonstrate erythrophagocytosis, but the presence of both naphtol-ASD-chloro-acetate esterase and butyrate esterase activities was similar to that seen in cases with t(8;16)(p11;p13). Involvement of the 8p11 region in ANLLM4 and M5 is discussed, being the third most frequent rearrangement in acute leukemia with monocytic components seen at our Center.     

Translocation (2;4)(p23;q25) An additional case of a new recurrent anomaly in acute myeloid leukemia

A second case of acute myeloid leukemia (AML) with a t(2;4)(p23;q25) as the sole anomaly is reported. Our case had a de novo AML (M2); the case previously described had AML (M2) post-MDS. It is suggested that t(2;4)(p23;q25) is a new, recurrent, but rare anomaly in AML.     

New recurrent balanced translocations in acute myeloid leukemia and myelodysplastic syndromes: Cancer and leukemia group B 8461

Acquired chromosome abnormalities in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the most valuable determinants of diagnosis and prognosis. In search of new recurrent balanced translocations, we reviewed the Cancer and Leukemia Group B (CALGB) cytogenetics database containing pretreatment and relapse karyotypes of 4,701 adults with AML and 565 with MDS who were treated on CALGB trials. We identified all cases with balanced structural rearrangements occurring as a sole abnormality or in addition to one other abnormality, excluded abnormalities known to be recurrent, and then reviewed the literature to determine whether any of what we considered unique, previously unknown abnormalities had been reported. As a result, we identified seven new recurrent balanced translocations in AML or MDS: t(7;11)(q22;p15.5), t(10;11)(q23;p15), t(2;12)(p13;p13), t(12;17)(p13;q12), t(2;3)(p21;p21), t(5;21)(q31;q22), and t(8;14)(q24.1;q32.2), and additionally, t(10;12)(p11;q15), a new translocation in AML previously reported in a case of acute lymphoblastic leukemia. Herein, we report hematologic and clinical characteristics and treatment outcomes of patients with these newly recognized recurrent translocations. We also report 52 unique balanced translocations, together with the clinical data of patients harboring them, which to our knowledge have not been previously published. We hope that once the awareness of their existence is increased, some of these translocations may become recognized as novel recurring abnormalities. Identification of additional cases with both the new recurrent and the unique balanced translocations will enable determination of their prognostic significance and help to provide insights into the mechanisms of disease pathogenesis in patients with these rare abnormalities. © 2012 Wiley Periodicals, Inc.