Trends in Molecular Medicine
ReviewReciprocal products of chromosomal translocations in human cancer pathogenesis: key players or innocent bystanders?
Section snippets
The reciprocal fusion product ABL–BCR is frequently expressed in CML and retains the BCR domain with GTPase-activating function
CML is a malignant myeloproliferative disease characterized by the hyperplasia of well differentiated myeloid cells and by its association with chromosomal translocation between chromosomes 9 and 22 [t(9;22)], which generates the Philadelphia (Ph) chromosome 10., 78.. This translocation creates two chimeric genes: the BCR–ABL on the derivative chromosome 22, and the ABL–BCR on the derivative chromosome 9 10., 11., 78.. The t(9;22) is the hallmark of CML. In 98% of CML patients it can be
Balanced or unbalanced forms of the t(X;17)(p11;q25) generating ASPL and TFE3 fusion genes are associated with distinct tumour types
Alveolar soft part sarcoma (ASPS) is a rare tumour that usually arises in the soft tissues of the upper and lower limbs [86]. It characteristically affects young adults (peak incidence age of between 15 and 35 years) and the majority of patients present advanced-stage disease. The disease has a relatively indolent clinical course but long-term mortality is high because of chemoresistance of metastatic disease [86]. ASPL has distinctive histopathological features: these tumours are made of oval
Concluding remarks
Although a considerable number of human cancers are associated with reciprocal chromosomal translocations, the detection of the products encoded by both derivatives is infrequent. Notably, however, the reciprocal product is more often expressed in hematological malignancies. Among the leukaemias, both products are frequently detected in APL and CML. Experimental data obtained in transgenic models of APL suggest that the expression of the reciprocal product influence disease penetrance,
Acknowledgements
We thank Marc Ladanyi for critical reading of the manuscript. This work is supported by the NCI, the De Witt Wallace Fund for Memorial Sloan-Kettering Cancer Center, the Mouse Model of Human Cancer Consortium (MMHCC), NIH Grants to P.P.P. and the Lymphoma and Leukemia Society of which P.P.P. is a Scholar. E.M.R. is the recipient of a grant from the ‘Fundação de Amparo a Pesquisa do Estado de São Paulo – FAPESP’ (Proc. 98/14247–6).
References (89)
The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice
Cell
(1986)Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia
Cell
(1987)The ABL–BCR fusion gene is expressed in chronic myeloid leukemia
Blood
(1993)Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt
Blood
(1992)Detection of DNA rearrangements in the AML1 and ETO loci and of an AML1/ETO fusion mRNA in patients with t(8;21) acute myeloid leukemia
Blood
(1993)Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party
Blood
(2000)Heterogeneity in CBF β/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16;16)(p13;q22) in acute myelogenous leukemia
Blood
(1995)A novel class of zinc finger/leucine zipper genes identified from the molecular cloning of the t(10;11) translocation in acute leukemia
Blood
(1995)The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family
Blood
(1998)AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia
Blood
(1995)
NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15)
Blood
A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia
Blood
Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation
Cell
Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor
Cell
The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion
Blood
Expression of the ABL–BCR fusion gene in Philadelphia-positive acute lymphoblastic leukemia
Blood
Primary renal neoplasms with the ASPL–TFE3 gene fusion of alveolar soft part sarcoma: a distinctive entity previously included among renal cell carcinomas of children and adolescents
Am. J. Pathol.
Molecular pathogenesis of acute promyelocytic leukemia
Semin. Hematol.
Altered myeloid development and acute leukemia in transgenic mice expressing PML–RARα under control of cathepsin G regulatory sequences
Blood
Two critical hits for promyelocytic leukemia
Mol. Cell
The diversity of BCR–ABL fusion proteins and their relationship to leukemia phenotype
Blood
ABL–BCR expression does not correlate with delations on the derivative chromosome 9 or survival in chronic myeloid leukemia
Blood
ABL–BCR expression in BCR–ABL-positive human leukemia cell lines
Leuk. Res.
Chromosomal translocations in human cancer
Nature
The role of chromosome translocations in leukemogenesis
Semin. Hematol.
Mechanisms of chromosomal translocations in B-cell lymphomas
Oncogene
Cloning and sequencing of a c-myc oncogene in a Burkitt's lymphoma cell line that is translocated to a germ line α switch region
Mol. Cell. Biol.
A translocated human c-myc oncogene is altered in a conserved coding sequence
Proc. Natl. Acad. Sci. U. S. A.
The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation
Nat. Genet.
Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma
Science
Frequent somatic hypermutation of the 5′ noncoding region of the BCL6 gene in B-cell lymphoma
Proc. Natl. Acad. Sci. U. S. A.
Expression pattern of the RARα/PML fusion gene in acute promyelocytic leukemia
Proc. Natl. Acad. Sci. U. S. A.
Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs
Proc. Natl. Acad. Sci. U. S. A.
Leucine-zipper dimerization motif encoded by the AF17 gene fused to ALL-1 (MLL) in acute leukemia
Proc. Natl. Acad. Sci. U. S. A.
The der(11) chromosome contains the critical breakpoint junction in the 4;11, 9;11, and 11;19 translocations in acute leukemia
Genes Chromosomes Cancer
Two distinct portions of LTG19/ENL at 19p13 are involved in t(11;19) leukemia
Oncogene
The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family
Proc. Natl. Acad. Sci. U. S. A.
Characterization of the translocation breakpoint sequences of two DEK–CAN fusion genes present in t(6;9) acute myeloid leukemia and a SET-CAN fusion gene found in a case of acute undifferentiated leukemia
Genes Chromosomes Cancer
An ets-related gene, ERG, is rearranged in human myeloid leukemia with t(16;21) chromosomal translocation
Proc. Natl. Acad. Sci. U. S. A.
Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations
Proc. Natl. Acad. Sci. U. S. A.
Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia
Nat. Genet.
The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein
Nat. Genet.
MOZ is fused to p300 in an acute monocytic leukemia with t(8;22)
Genes Chromosomes Cancer
Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11
Oncogene
Cited by (37)
Mouse models of MLL leukemia: Recapitulating the human disease
2017, BloodCitation Excerpt :For example, the t(4;11)(q21;q23) translocation (or t(4;11) for short) can produce both an MLL-AF4 (5′-MLL translocation) and an AF4-MLL (3′-MLL translocation) fusion, both of which can produce functional proteins.2 In many MLLr patients, the 3′-MLL translocation either is not in frame1,3 or does not produce a detectable transcript,3-5 whereas transcripts from the 5′-MLL translocation are detected in 100% of patients.3-7 Although 3′-MLL translocations can have oncogenic potential,7,8 the 5′-MLL translocation is usually considered to be the main driver of MLL leukemogenesis.
Dynamics of Tumor Heterogeneity Derived from Clonal Karyotypic Evolution
2015, Cell ReportsCitation Excerpt :This was also the case within the subset of derivative chromosomes (odds ratio = 93.3, p < 0.0001) (Figure 6H). Collectively, these data demonstrate that derivative chromosomes are subject to strong selective pressures in chromosomally unstable cancers, and they address a long-standing question regarding the fate of reciprocal products of chromosomal translocation events, and why such products are frequently lost in solid tumors (Rego and Pandolfi, 2002). We have developed a stochastic model of clonal karyotypic evolution to explore, in silico, the dynamics by which numerical chromosomal changes contribute to clonal and subclonal fitness and diversification.
Significance of AF4-MLL reciprocal fusion in t(4;11) leukemias?
2011, Leukemia ResearchA pericentric inv(9)(p22q34) of the der(9)t(9;22)(q34;q11.2) is a recurrent secondary anomaly in Ph-positive leukemia
2010, Cancer Genetics and CytogeneticsCitation Excerpt :However, it has been pointed out that the reciprocal products of chromosomal translocations may enhance or change the activities of a fusion protein. One example is the RARα-PML fusion protein in acute promyelocytic leukemia [9]. Wang et al. [10] reported a Ph-positive CML patient with a standard translocation t(9;22)(q34;q11.2).