dup(1q) in ALL

2017-05-01   Anwar N. Mohamed 

1.Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA; amohamed@dmc.org


Review on duplication of 1q in acute lymphoblastic leukemia, with data on clinics, and the genes involved.

Clinics and Pathology


Acute Lymphoblastic Leukemia (ALL)


Duplication or gain of 1q may result from a partial interstitial duplication of 1q or more often from an unbalanced translocation (Figure 1, 2). Although dup(1q) is rarely seen as a sole abnormality, it is mostly found in association with well-known primary cytogenetic abnormalities. In high hyperdiploid ALL, duplication of 1q is the most frequent structural aberration found in approximately 15% cases (Figure 1). Gain of 1q is also associated with t(1;19) translocation; 75% of those cases have an unbalanced translocation leading to gain/trisomy 1q. Additionally, partial trisomy of 1q is found in almost 25% of Burkitt lymphoma/leukemia (BL) cases in particular the endemic type. Therefore, duplication/gain of 1q in ALL is an apparently a secondary event.
The size of the duplicated region of 1q is variable but mostly reported form 1q21 -> qter. Using array CGH, Davidsson et al studied ten cases with duplicated 1q; six cases of B-cell precursor pediatric high hyperdiploid ALL and four cases of BL. The proximal breakpoints in all cases were near the centromere, mostly clustering within a 1.4 Mb segment at 1q12-21.1. There was no evidence hypomethylation of sat II DNA in ALLs with or without 1q gains indicating that aberrant methylation was not involved in the formation of dup(1q), as previously suggested for other neoplasms with 1q rearrangements. However, the 1q distal breakpoints were heterogeneous, being more distal in the ALLs than in the BLs. Thus, the minimally gained segment was larger in the ALLs (57.4 Mb) than in the BLs (35 Mb), corresponding to dup(1)(q22q32.3) and dup(1)(q12q25.2), respectively.


The presence of dup(1q) has no effect on the outcome of ALL patients with high hyperdiploidy (Paulsson et al, 2013). It is unclear yet whether the presence of balanced or unbalanced t(1;19)(q23;p13.3) in ALLs has an effect on the prognosis.

Genes Involved and Proteins

The molecular characterization of dup(1q) in ALL is not well-defined and very limited data is available. However, the unbalanced nature of dup(1q) suggests that gene dosage effect is likely contribute to the neoplastic process. Nevertheless, gene expression profile revealed that five genes, DAP3, B4GALT3, UCK2, RGS16 and TMEM183A were significantly up-regulated in high hyperdiploid ALL carrying dup(1q) compared to those without dup(1q). DAP3 and UCK2 genes were among the highly expressed in BL with gain of 1q (Davidsson et al 2007).
Gene name
DAP3 (death associated protein 3)
Alternative symbol MRPS29 (mitochondrial ribosomal protein S29).
Protein description
DAP3 gene is transcribed into a 1.7-kb mRNA and translates into a 46 kDa protein located in the lower area of the small mitoribosomal subunit. This protein contains a P-loop motif that binds GTP and a highly conserved 17-residue targeting sequence responsible for its localization to the mitochondria. Many of the phosphorylation sites on this protein are highly conserved and clustered around GTP-binding motifs. DAP3 forms an important portion of the a 28S subunit protein of the mitochondrial ribosome and plays key roles in translation, cellular respiration, and apoptosis. The protein is normally reserved inactive as phosphoprotein. When activated, it co-localizes with FADD and participates in the formation of the death inducing signaling complex (DISC). Recent studies suggests that DAP3 is strongly associated with the Fas receptor related DISC. It is presumed that DAP3 may have tumor suppressant role predicated by its function as a pro-apoptotic molecule. Counterintuitively, DAP3 has a pro-survival role in mitochondrial function. The current literature places DAP3 at the link of several highly significant and occasionally antagonistic pathways (Kissil JL et al 1995, 1998).
It encodes a 261 amino-acid protein with a predicted molecular mass of 29 kDa. It is an enzyme, catalyzes the phosphorylation of uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP), respectively. UCK2 has only been detected in human placental tissue and overexpressed in various tumor cells, including neuroblastoma. Recent studies suggest that UCK2 could be used as a selective target for chemotherapy delivery in neuroblastoma cells expressing this specific isoform of UCK while sparing normal tissues (van Kuilenburg and Meinsma 2016).
Gene name
RGS16 (regulator of G protein signaling 16)
Protein description
This gene encodes protein belongs to the regulator of G protein signaling family. It inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits. Also it may play a role in regulating the kinetics of signaling in the phototransduction cascade. The RGS family, comprising 22 homologues of proteins, plays a role in cellular proliferation, differentiation, membrane trafficking, and embryonic development through the involvement of the mitogen-activated protein kinase signalling pathway. The activity and specificity of Rgs16 protein are regulated through phosphorylation, in which several oncogenes are involved, by modulating the phosphorylation on a tyrosine residue in the RGS box. Previous studies showed that RGS16 is overexpressed in high hyperdiploid ALL and several other cancers such as CRC. Patients with RGS16 high-expression had a poorer overall survival rate than patients with low-expression suggesting that RGS16 is useful as a predictive marker for patient prognosis of CRC (Miyoshi et al 2009).
Gene name
TMEM183A (transmembrane protein 183A)
Dna rna description
UCK2 gene contains 7 exons and spans over 19 kb
Also known C1orf37
Dna rna description
The TMEM183A is the parental gene of TMEM138B, which is a young gene derived through retroposition after the divergence of human and chimpanzee. There are only 6 nucleotide changes in the coding region between TMEM183A and TMEM183B genes (Yu et al 2006).


Pubmed IDLast YearTitleAuthors
244033092014β-1,4-Galactosyltransferase III suppresses β1 integrin-mediated invasive phenotypes and negatively correlates with metastasis in colorectal cancer.Chen CH et al
176135362007Tiling resolution array comparative genomic hybridization, expression and methylation analyses of dup(1q) in Burkitt lymphomas and pediatric high hyperdiploid acute lymphoblastic leukemias reveal clustered near-centromeric breakpoints and overexpression of genes in 1q22-32.3.Davidsson J et al
74992681995Isolation of DAP3, a novel mediator of interferon-gamma-induced cell death.Kissil JL et al
96792461998Death-associated proteins: from gene identification to the analysis of their apoptotic and tumour suppressive functions.Kissil JL et al
114898302001Death-associated protein 3 (Dap-3) is overexpressed in invasive glioblastoma cells in vivo and in glioma cell lines with induced motility phenotype in vitro.Mariani L et al
197600452009RGS16 is a marker for prognosis in colorectal cancer.Miyoshi N et al
236456892013High modal number and triple trisomies are highly correlated favorable factors in childhood B-cell precursor high hyperdiploid acute lymphoblastic leukemia treated according to the NOPHO ALL 1992/2000 protocols.Paulsson K et al
222877612012The mRNA expression of DAP3 in human breast cancer: correlation with clinicopathological parameters.Wazir U et al
258835352015The role of death-associated protein 3 in apoptosis, anoikis and human cancer.Wazir U et al
166448692006Origination and evolution of a human-specific transmembrane protein gene, c1orf37-dup.Yu H et al
272397012016The pivotal role of uridine-cytidine kinases in pyrimidine metabolism and activation of cytotoxic nucleoside analogues in neuroblastoma.van Kuilenburg AB et al


Atlas Image
Top: G-banded hyperdiploid karyotype with duplication 1q from an ALL case. Bottom: G-banded hyperdiploid karyotype fom ALL patient showing an unbalanced der(1;6)(q10;p10) resulting in gain/trisomy 1q.
Atlas Image
dup(1q) in ALL Fluorescence in situ hybridization with Vysis LSI 1p36/LSI 1q25 dual-color probe (Abbott molecular, US) showing 2 normal copies of 1q25 on normal (A) and 3 copies of green signal on metaphase with 1q duplication (B) and on metaphase with inverted 1q duplication (C). Partial karyotypes and metaphase with C-band showing the inverted duplication of 1q (D) Courtesy Adriana Zamecnikova.


Anwar N. Mohamed

dup(1q) in ALL

Atlas Genet Cytogenet Oncol Haematol. 2017-05-01

Online version: http://atlasgeneticsoncology.org/haematological/1049/dup(1q)-in-all