Acute leukemia with t(1;3)(p36;q21), evolution to t(1;3)(p36;q21), t(14;17)(q32;q21), and loss of red cell A and Le(b) antigens.

At transformation of refractory anemia with ring sideroblasts to acute nonlymphocytic leukemia (ANLL) the bone marrow cells of a 75-year-old woman showed three different karyotypes, i.e., 46,XX,46,XX,t(1;3)(p36;q21) and 46,XX,t(1;3)(p36;q21),t(14;17)(q32;q21). She received no antileukemic therapy, and 1 year later, all her bone marrow cells were t(1;3)(p36;q21),t(14;17)(q32;q21). In association with the onset and first 11 months of ANLL, the platelet count increased 10-fold to a peak of 750 x 10(9)/L, providing further evidence that the t(1;3)(p36;q21) translocation causes stimulation of thrombopoiesis. Six months after transformation, her red cells showed reduced expression of A and Leb antigens. Serum alpha-n-3-acetylgalactosaminyl transferase (blood group A transferase) and red cell adenylate kinase were both reduced. The genes for both these substances are at 9q34, which suggests an abnormality here, although cytogenetically chromosome 9 appeared normal. This is the first case with t(1;3)(p36;q21) to show concurrent loss of red cell antigens and the first report detailing the course of untreated ANLL with t(1;3)(p36;q21).     

Translocation t(1;3)(p36;q21) in malignant myeloid stem cell disorders

A t(1;3)(p36;q21) translocation was found in bone marrow samples of two patients with hematologic disorders. One patient had a myelodysplastic syndrome evolving into acute nonlymphocytic leukemia (ANLL) M1 and the second patient had ANLL-M6 secondary to treatment for Hodgkin's disease. Because myelodysplastic syndromes and secondary leukemia are stem cell disorders, the t(1;3)(p36;q21) appears to be a chromosome abnormality in malignant myeloid stem cells.     

Translocation (1;3)(p36;q21) in secondary leukemia

A case of acute nonlymphocytic leukemia (M4) secondary to treatment for multiple myeloma is described. The patient presented a translocation t(1;3)(p36;q21) and monosomy 7.     

Second relapse of acute promyelocytic leukemia (ANLL-M3) with t(15;17) and t(1;3)(p36;q21).

We describe herein a patient with acute promyelocytic leukemia (APL)-(ANLL-M3) whose bone marrow cells in the second relapse showed t(1;3)(p36;q21) together with t(15;17) (q22;q11-q12). Although a total of 21 patients with t(1;3) have been reported so far, among which three cases with de novo acute nonlymphocytic leukemia were included, our patient is the first case with APL. The hematologic findings in our case confirmed the previous observations that this anomaly is associated with relatively high platelet count and the multi-myeloid lineage involvement of leukemic cells. Our patient responded well to chemotherapy and achieved first and second remission with 42 months of total survival, contrary to our expectation that patients with this anomaly have a poor prognosis.     

Diagnostic and prognostic significance of t(1;3)(p36;q21) in the disorders of hematopoiesis

We describe a cytogenetic abnormality with important diagnostic and prognostic implications. The translocation t(1;3)(p36;q21) is an acquired chromosomal rearrangement associated with myelodysplastic syndromes, which have a high propensity for conversion to refractory acute nonlymphocytic leukemia.     

t(1;3)(p36;p21) is a recurring therapy-related translocation

Chromosome bands 1p36 and 3p21 are known to be recurring breakpoints in therapy-related (t-) leukemia. We identified a recurring translocation, t(1;3)(p36;p21), in eight patients with various hematologic malignancies: three patients with ALL, one with chronic myelogenous leukemia (CML) in accelerated phase (AP), two with MDS, and two with AML(M3). Five of the eight patients had a history of chemotherapy, including alkylating agents in three, before the translocation was detected. In two of these five patients, the t(1;3)(p36;p21) emerged only at relapse or in the accelerated phase of CML. The karyotypes of the patients were complex, including -7 and structural abnormalities of 5q, 6q, 7q, 9p, and 11q23. Survival time varied among patients (25 days to more than 16 years). Using FISH with 13 1p35-36 cosmid probes (tel-FB12-CA5-G7-FD2-CB1-ED8-FD9-G32-AE3-G50-AD8-GG4-G43-cen), we delineated the 1p36 breakpoint in two patients with MDS and ALL as lying between FB12 and FD2 (between BAC47P3 and PAC963K15), with a small deletion near the breakpoint in both cases. In the patient with MDS, there was also a deletion at 3p21.3, as detected with the cosmid probe cosNRL9. The results of the present study suggest that t(1;3)(p36;p21) in hematologic diseases is associated with prior exposure to mutagens, including alkylating agents.     

Identification of a yeast artificial chromosome spanning the 8q12 translocation breakpoint in pleomorphic adenomas with t(3;8)(p21;q12)

A subgroup of pleomorphic adenomas of the salivary glands is characterized by translocations involving chromosome 8, with consistent breakpoints at 8q12. As part of a positional cloning effort to isolate the gene(s) affected by these translocations we now report the mapping of the 8q12 breakpoint in two primary pleomorphic adenomas with the recurrent t(3;8)(p21;q12). Yeast artificial chromosome (YAC) clones corresponding to eight different loci in 8q11-12 were isolated and mapped by fluorescence in situ hybridization (FISH). The t(3;8) breakpoint was mapped within a 1 Mb region flanked by MOS proximally and by the genetic marker D8S166 distally. One YAC within this region was shown to span the t(3;8) breakpoint in two tumors. This YAC will provide an excellent tool for isolating the gene(s) at the breakpoint(s) in adenomas with t(3;8). Genes Chromosom Cancer 17:166–171 (1996). © 1996 Wiley-Liss, Inc.     

Constitutional translocation t(3;6)(p14;p11) in a family with hematologic malignancies

We describe a family with an inherited constitutional balanced translocation t(3;6)(p14;p11) and hematologic malignancies. Of two proven translocation carriers, one had acute myeloid leukemia and the other had myelofibrosis. A third member who had died of acute leukemia was a possible translocation carrier (chromosome analysis had not been performed). Five healthy translocation carriers were detected. Neither the translocation nor additional hematologic malignancies were found outside the nuclear family. It could not be definitely clarified if this constitutional translocation predisposes to hematologic malignancies. Breakpoint 3p14 has previously been implicated in recurrent cancer-associated rearrangements but 6p11 has not. We suggest that other investigators look for involvement of these breakpoints in cancer patients.     

Girl with monosomy 1p36 and Angelman syndrome due to unbalanced der(1) transmission of a maternal translocation t(1;15)(p36.3;q13.1)

We report on a girl with monosomy 1p36.3 and Angelman syndrome due to an unbalanced transmission of a maternal balanced chromosomal translocation. She manifested monosomy 1p36 and Angelman syndrome including generalized hypopigmentation, ataxic movements, intractable seizures with characteristic electroencephalographic (EEG) abnormality compatible with Angelman syndrome, and other minor anomalies, large anterior fontanelle, severe psychomotor retardation, and seizures due to monosomy 1p36. Her karyotype was 45, XX, der(1) t(1;15)(p36.31;q13.1),-15, derived from maternal translocation. Molecular analysis determined a breakpoint of 1p between D1S243 and D1S468, which suggested that most genes contributing to the common phenotype are in the distal region.     

T-cell acute lymphoblastic leukemia with t(1;18)(p36;q22)

An 8-year-old white boy with a T-cell acute lymphoblastic leukemia (T-ALL) developed chromosomal abnormalities t(1;18)(p36;q22) and del (6)(q21) at the first bone marrow relapse. Rearrangements of the chromosome region 1p36 have been reported previously in adults with T-ALL.     

Transformation of polycythemia vera to acute nonlymphocytic leukemia accompanied by t(1;3)(p36;q21) karyotype

The case of a patient with a history of polycythemia vera and 46,XX karyotype who transformed into acute nonlymphocytic leukemia with 46,XX,t(1;3)(p36;q21) rearrangement is reported. Significant percentages of the circulating blasts in the peripheral blood were positive on immunocytochemical stains for megakaryocyte markers, anti-Factor VIII, and antiglycoprotein IIb/IIIa. On the basis of our studies and published reports, trilineage hematopoietic abnormalities and a poor response to therapy may represent typical features of patients with t(1;3).     

Unexpected complexity at breakpoint junctions in phenotypically normal individuals and mechanisms involved in generating balanced translocations t(1;22)(p36;q13)

Approximately one in 500 individuals carries a reciprocal translocation. Balanced translocations are usually associated with a normal phenotype unless the translocation breakpoints disrupt a gene(s) or cause a position effect. We investigated breakpoint junctions at the sequence level in phenotypically normal balanced translocation carriers. Eight breakpoint junctions derived from four nonrelated subjects with apparently balanced translocation t(1;22)(p36;q13) were examined. Additions of nucleotides, deletions, duplications, and a triplication identified at the breakpoints demonstrate high complexity at the breakpoint junctions and indicate involvement of multiple mechanisms in the DNA breakage and repair process during translocation formation. Possible detailed nonhomologous end-joining scenarios for t(1;22) cases are presented. We propose that cryptic imbalances in phenotypically normal, balanced translocation carriers may be more common than currently appreciated.     

Translocation t(9;9)(p13;q34) in Philadelphia-negative chronic myeloid leukemia with breakpoint cluster region rearrangement

Chromosome analysis showed a t(9;9)(p13;q34) in a patient with chronic myeloid leukemia (CML) without a Philadelphia (Ph) chromosome in all examined cells. Southern blot analysis of leukocyte DNA revealed rearrangement of breakpoint cluster region (bcr) within the 5.8-kb bcr sequences as in Ph-positive CML patients. The findings confirm that the 9q34 and 22q11 bands are always involved in CML independent of the chromosomal evidence. It is suggested that Ph-negative bcr-positive CML may have variant translocations, as in the case of the t(9;9) reported here.     

The t(1; 12)(p36;q13) in a Renal Oncocytoma

A new chromosome rearrangement, t(1;12)(p36;q13). is added to the cytogenetic changes found in renal oncocytomas. The breakpoint in 12q is cytogenetically different from those of the MAR region, and molecularly HMGlC located in 12q 15 on the basis of 3′ RACE experiments does not seem to be directly involved. Genes Chrornosorn Cancer l7:/36–/39 (1996). © 1996 Wiley-Lia, Inc.     

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.     

Acute nonlymphocytic leukemia with a translocation (1;3)(p36;q21) in an XYY man

Neoplastic disease is quite rare in an XYY syndrome. We report the fifth known case, who suffered from acute nonlymphocytic leukemia (ANLL). Cytogenetic study of his bone marrow revealed a new chromosomal translocation (1;3)(q36;q21), which has only recently been described in patients with myelodysplastic syndrome.