t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy- related myelodysplastic syndrome and acute myeloid leukemia

Abstract

We have identified an identical reciprocal translocation between the long arms of chromosomes 3 and 21 with breakpoints at bands 3q26 and 21q22, [t(3;21)(q26;q22)], in the malignant cells from five adult patients with therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML). Primary diagnoses were Hodgkin's disease in two patients and ovarian carcinoma, breast cancer, and polycythemia vera in one patient each. Patients had been treated with chemotherapy including an alkylating agent for their primary disease 1 to 18 years before the development of t-MDS or t-AML. We have not observed the t(3;21) in over 1,500 patients with a myelodysplastic syndrome or acute myeloid leukemia arising de novo or in over 1,000 patients with lymphoid malignancies. We have previously reported that the t(3;21) occurs in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Thus, the t(3;21) appears to be limited to t-MDS/t-AML and CML, both of which represent malignant disorders of an early hematopoietic precursor cell. These results provide a new focus for the study of therapy-related leukemia at the molecular level.

AMLI fusion transcripts in t(3;21) positive leukemia: Evidence of molecular heterogeneity and usage of splicing sites frequently involved in the generation of normal AMLI transcripts

“…Our study and the recent work of others (Nucifora et al, 1993c;Mitani et al, 1994) provide evidence of molecular heterogeneity in the (3;21) (q26;qZZ) associated with various leukemia subtypes (Schneider et al, 1991). T h e t(3;21) is found in the blastic crisis of CML (Rubin et al, 1987;Coyle and Nayfeld, 1988), in leukemia evolving from (therapy-related) myelodysplasia (Rubin et al, 1990), and in leukemia following other hematopoietic proliferative diseases (Dastugue et al, 1990). It has been suggested that the t(3;21) has a b 0 -C TTG GGG CIG GTA CAC CCl' CC4 Gcx: TGG TAC ACC CTC CAG G C T GGT AT.4 Crc AGG GAC CAT GTC TCA )His Leu G l y Leu V a l His Pro Pro G l y T r p '&r Thr Leu G l n A l a G l y Ile Leu Arg Asp His V a l Ser GAT 'TCC TE GGT TCA ACC T I T CCC CCA GGG GGA 'IW: C>G GCC CCC GTA h4G CCA 9.AA AGT )Asp Ser Leu G l y Ser Thr Phe Pro Pro G l y G l y T r p G l n A l a Pro V a l L y s Pro L y s Ser critical role in the progression from a preleukemic to a leukemic state since it has rarely been observed in de novo acute myelocytic leukemia (Rubin et al, 1990).…”

Development of a dual‐color, double fusion FISH assay to detect RPN1/EVI1 gene fusion associated with inv(3), t(3;3), and ins(3;3) in patients with myelodysplasia and acute myeloid leukemia

“…Rearrangements of the long arm of chromosome 3, involving the 3q21 and 3q26.2 regions, have been observed in de novo acute myeloid leukemia (AML), AML with antecedent myelodysplastic syndrome and aggressive subtypes of myelodysplasia (MDS) [1–4]. Although several nonrandom, recurrent translocations involving 3q21 and 3q26.2 have been described, the most common rearrangements involve simultaneous disruption of 3q21 and 3q26.2 as the result of inv(3)(q21q26.2) [inv(3)], t(3;3)(q21;q26.2) [t(3;3)], and less commonly ins(3;3)(q26.2;q21q26.2) [ins(3;3)] [5–9]. The end result of each of these rearrangements is the juxtaposition of the RPN1 gene at 3q21 with the EVI1 ( MECOM ) gene at 3q26.2 [10].…”

Molecular characterization of the genomic breakpoints in a case of t(3;21)(q26;q22)

“…Although several genes structurally or transcriptionally altered by translocations have been identified, the molecular mechanisms underlying such translocations are poorly understood. The t(3;21)(q26;q22) is a recurring abnormality in blastic crisis of chronic myelogenous leukemia (CML) (Rubin et al, 1987;Coyle and Najfeld, 1988), leukemia developed from myelodysplastic syndrome (MDS; Rubin et al, 1990), and therapy-related leukemia (Dastugue et al, 1990), but rarely occur in de novo acute myelogenous leukemia (AML; Rubin et al, 1990), suggesting that the appearance of this chromosomal abnormality may be a key event when hematological disorders transform to acute leukemia (Chen et al, 1991). Molecular cloning and cytogenetic analysis indicate that the breakpoints are heterogeneous even within a specific clinical phenotype (Nucifora et al, 1993(Nucifora et al, , 1994Mitani et al, 1994;Sacchi et al, 1994).…”

“…Notably, the t(3;21) breakpoints involve the AML1 gene known to be rearranged in t(8;21) associated with AML (Miyoshi et al, 1991;Mitani et al, 1994) and in t(12;21) associated with acute lymphoblastic leukemia (ALL) (Golub et al, 1995;Romana et al, 1995). Although t(8;21) and t(12;21) are frequently detected in de novo AML and ALL, respectively, t(3;21) is frequently associated with therapy-related AML (Keldsen et al, 1987;Rubin et al, 1990;Quesnel et al, 1993). These findings suggest that the genetic recombination mechanisms causing the 21q22 translocation may be different among the translocations of de novo AML, blastic crisis of CML, and therapyrelated leukemias.…”