A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

Abstract

Although many of the chromosomal abnormalities in hematologic malignancies are identifiable cytogenetically, some are only detectable using molecular methods. We describe a novel cryptic t(7;21)(p22;q22) in acute myeloid leukemia (AML). FISH, 3 0 RACE, and RT-PCR revealed a fusion involving RUNX1 and the ubiquitin-specific protease (USP) gene USP42. The genomic breakpoint was in intron 7 of RUNX1 and intron 1 of USP42. The reciprocal chimera was not detected -neither on the transcriptional nor on the genomic level -and FISH showed that the 5 0 part of USP42 was deleted. USP42 maps to a 7p22 region characterized by segmental duplications. Notably, 17 kb duplicons are present 1 Mb proximal to USP42 and 3 Mb proximal to RUNX1; these may be important in the genesis of t (7;21). This is the second cryptic RUNX1 translocation in hematologic malignancies and the first in AML. The USPs have not previously been reported to be rearranged in leukemias. The cellular context in which USP42 is active is unknown, but we here show that it is expressed in normal bone marrow, in primary AMLs, and in cancer cell lines. Its involvement in the t(7;21) suggests that deregulation of ubiquitin-associated pathways may be pathogenetically important in AML.

The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO

“…1,2 AML1 is also the major gene involved in chromosomal translocations in leukemia, 3,4 seen translocated in both lymphoid and myeloid leukemia, such as t(8;21) (AML1-ETO), 5 t(3;21) (AML1-Evi1), 6 t(12;21) (TEL-AML1), 7 t(16;21) (AML1-MTG16), 8 t(12;21) (AML1-copine VIII), 9 t(X;21) (AML1-Fog2), 10 and t(7;21) (AML1-USP42). 11 Specifically the AML1-ETO-associated translocation is observed in approximately 40% of cases of acute myeloid leukemia of the M2 classification (AML-M2), while present in approximately 12% of AMLs. This translocation protein contains the N-terminal portion of AML1 up to its Runt homology DNA-binding domain fused to most of the ETO (MTG8) protein.…”

Cryptic chromosomal aberrations waiting to be discovered

“…We now know that a significant fraction of the patients with normal karyotype, do harbor chromosomal rearrangements that escape detection by routine cytogenetics, as again highlighted by the study of Paulsson et al 1 in this issue of Leukemia. Well known examples include the t(12;21)(p13;q22)/ ETV6-RUNX1 fusion in B-cell acute lymphoblastic leukemia (B-ALL), 2 the t(5;14)(q35;q32)/TLX3 overexpression, and the recently discovered episomes (small extrachromosomal elements) carrying the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia (T-ALL), 3 and the del(4)(q12q12)/ FIP1L1-PDGFRA fusion in chronic eosinophilic leukemia (CEL).…”

Ubiquitylation in normal and malignant hematopoiesis: novel therapeutic targets

“…21 Recently, the DUB USP42 was identified in a translocation with RUNX1 in acute myeloid leukemia (AML). 22 Its involvement in this translocation suggests that deregulation of ubiquitin-associated pathways may be important in leukemogenesis.…”