Leukemias are frequently characterized by the presence of chromosomal rearrangements, but 40–50% of these malignancies present with a normal karyotype, as determined by standard cytogenetic analysis. 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).4 Sophisticated methods, such as microarray-comparative genomic hybridization (array-CGH) and single nucleotide polymorphism (SNP)-arrays are expected to uncover more cryptic aberrations in leukemia, including cryptic deletions and amplifications, as well as uniparental disomy, as nicely demonstrated by pioneering work by Brian Young et al.5, 6, 7 However, despite the high resolution of the current CGH- and SNP-arrays, these methods are unable to detect balanced chromosomal translocations that are not associated with DNA losses or gains. Fluorescence in situ hybridization (FISH) with gene-specific probes or multicolor FISH (M-FISH)8 is required to detect cryptic balanced chromosomal aberrations. Using M-FISH, Speleman and co-workers recently identified novel aberrations in ALL, also leading to the identification of a recurrent cryptic inv(7)(p15q34) in T-ALL,9, 10 and a specific FISH screen looking for ABL1 rearrangements in T-ALL revealed a novel cryptic t(9;14)(q34;q32).11 In this issue of Leukemia, M-FISH revealed the presence of a novel cryptic translocation t(7;21)(p22;q22), involving the well known RUNX1 oncogene, and USP42, a gene encoding a ubiquitin specific protease, a family of proteins not previously implicated in the pathogenesis of leukemia.1
RUNX1 is an extraordinary gene. This gene is involved in several chromosomal translocations,12 with the most common being the t(12;21), generating the ETV6-RUNX1 (TEL-AML1) fusion gene in B-ALL,2 and the t(8;21), generating the RUNX1-RUNX1T1 (AML1-ETO) fusion gene in acute myeloid leukemia (AML).13 In addition, RUNX1 is mutated in ∼20% of AML-M0, and at lower frequency in other AML subtypes and other hematological malignancies,14 and haploinsufficiency of RUNX1 causes familial thrombocytopenia.15 RUNX1 is ubiquitously expressed in the hematopoietic system and encodes a subunit of the heterodimeric transcription factor core-binding factor (CBF). CBF, consisting of RUNX1 and CBFB, is important for the regulation of a number of genes important for hematopoiesis.16 Leukemia associated RUNX1 fusion proteins are believed to interfere with this transcriptional activation, and thereby resulting in an impairment of hematopoietic cell differentiation.13, 17
Unlike RUNX1, the partner gene in this novel fusion described by Paulsson et al.1 is a less well characterized protein, USP42, which belongs to the ubiquitin specific protease family. Ubiquitin is a highly conserved polypeptide found in all eukaryotes that is covalently attached to target proteins by a complex including ubiquitin-protein ligases (E3's). One of the functions of ubiquitin is to target proteins for complete or partial degradation by a protein complex called the proteasome.18 More recently, it was shown that a large family of ubiquitin specific proteases (USPs) exists that are able to perform the opposite reaction, and specifically cleave covalently linked ubiquitin from specific target proteins. As a consequence, the action of ubiquitin specific proteases may lead to decreased ubiquitination and protein stabilization, as has been described for USP7 in relation with TP53 (p53) stabilization.19 The tumor suppressor protein TP53 is a short-lived protein that is maintained at low levels in normal cells by Mdm2-mediated ubiquitination and subsequent proteolysis. The ubiquitin specific protease USP7 was shown to de-ubiquinate TP53 and as such be important for its stabilization and its tumor suppressor function.19 USPs are also important during myeloid differentiation. Overexpression of USP18 (also named UBP43) was shown to block cytokine-induced terminal differentiation of monocytic cells, suggesting that USP18 plays an important role in hematopoiesis by modulating the ubiquitin-dependent proteolytic pathway or the ubiquitination state of important regulatory factors during myeloid cell differentiation.20
Specific examples of USPs in the pathogenesis of leukemia have not been described yet, but the observation that ubiquitin-specific protease 33 (USP33) is over-expressed in B-ALL relative to T-ALL,21 and the identification of the RUNX1-USP42 fusion gene described in this issue of Leukemia,1 may implicate ubiquitin-specific proteases as novel players in leukemogenesis. The novel RUNX1-USP42 fusion protein could act as a deregulated transcription factor through the presence of the RUNT domain of RUNX1 that is both a DNA-binding domain and the domain required for interaction with CBFB. An attractive option, however, is that RUNX1-USP42 also acts as true USP. Since this chimeric USP can now interact with CBFB (and other RUNX1 interaction partners), the RUNX1-USP42 protein could exert part of its oncogenic function through de-ubiquitination of RUNX1-associated proteins or other proteins important for the differentiation of myeloid cells. Future work may reveal more alterations of genes encoding ubiquitin specific proteases or related proteins in leukemia, and since we have not yet observed them, these may be other examples of cryptic chromosomal aberrations waiting to be discovered.
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Jan Cools is a postdoctoral researcher of the FWO-Vlaanderen. Supported by the FWO-Vlaanderen, the Belgian Federation against Cancer, and the European Hematology Association.
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Lahortiga, I., Cools, J. Cryptic chromosomal aberrations waiting to be discovered. Leukemia 20, 210–211 (2006). https://doi.org/10.1038/sj.leu.2404078