Overexpression of chromatin remodeling and tyrosine kinase genes in iAMP21-positive acute lymphoblastic leukemia

Öfverholm, Ingegerd Ivanov; Zachariadis, Vasilios; Taylan, Fulya; Marincevic-Zuniga, Yanara; Tran, Anh Nhi; Saft, Leonie; Nilsson, Daniel; Syvänen, Ann‐Christine; Lönnerholm, Gudmar; Harila‐Saari, Arja; Nordenskjöld, Magnus; Heyman, Mats; Nordgren, Ann; Nordlund, Jessica; Barbany, Gisela

doi:10.1080/10428194.2019.1678153

Cited by 8 publications

(13 citation statements)

References 59 publications

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“…However, the resolution of the algorithm might be too low to reliably detect iAMP21. We thus, analyzed the expression of DYRK1A and CHAF1B that have recently been associated with iAMP21-positive ALLs [ 33 ]. The expression of both genes was indeed heightened in the iAMP21 case (Additional file 2 : Fig.…”

Section: Resultsmentioning

confidence: 99%

Clinical application of whole transcriptome sequencing for the classification of patients with acute lymphoblastic leukemia

et al. 2021

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Background Considering the clinical and genetic characteristics, acute lymphoblastic leukemia (ALL) is a rather heterogeneous hematological neoplasm for which current standard diagnostics require various analyses encompassing morphology, immunophenotyping, cytogenetics, and molecular analysis of gene fusions and mutations. Hence, it would be desirable to rely on a technique and an analytical workflow that allows the simultaneous analysis and identification of all the genetic alterations in a single approach. Moreover, based on the results with standard methods, a significant amount of patients have no established abnormalities and hence, cannot further be stratified. Methods We performed WTS and WGS in 279 acute lymphoblastic leukemia (ALL) patients (B-cell: n = 211; T-cell: n = 68) to assess the accuracy of WTS, to detect relevant genetic markers, and to classify ALL patients. Results DNA and RNA-based genotyping was used to ensure correct WTS-WGS pairing. Gene expression analysis reliably assigned samples to the B Cell Precursor (BCP)-ALL or the T-ALL group. Subclassification of BCP-ALL samples was done progressively, assessing first the presence of chromosomal rearrangements by the means of fusion detection. Compared to the standard methods, 97% of the recurrent risk-stratifying fusions could be identified by WTS, assigning 76 samples to their respective entities. Additionally, read-through fusions (indicative of CDKN2A and RB1 gene deletions) were recurrently detected in the cohort along with 57 putative novel fusions, with yet untouched diagnostic potentials. Next, copy number variations were inferred from WTS data to identify relevant ploidy groups, classifying an additional of 31 samples. Lastly, gene expression profiling detected a BCR-ABL1-like signature in 27% of the remaining samples. Conclusion As a single assay, WTS allowed a precise genetic classification for the majority of BCP-ALL patients, and is superior to conventional methods in the cases which lack entity defining genetic abnormalities.

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Section: Resultsmentioning

confidence: 99%

Clinical application of whole transcriptome sequencing for the classification of patients with acute lymphoblastic leukemia

et al. 2021

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“…A recent study from Öfverholm et al (17) identified MORC3, SON, CHAF1B and DYRK1A as potential candidates for the iAMP21 pathophysiology. In our study, MORC3, CHAF1B, and DYRK1A, located in the CRA, were upregulated, but less strongly than RIPPLY3 (CHAF1B: R = 0.32) or not at all correlated to the iAMP21 signature (MORC3: R = -0.034; DYRK1A: R = 0.004).…”

Section: Discussionmentioning

confidence: 99%

“…However, Rand et al (4) show that the amplification is not completely random, with a region that is amplified in 18 studied cases of 5.1 Mb spanning from 32.8 to 37.9 Mb (hg18). This amplified region contains 86 genes (coding and non-coding) (4), and even though some of these genes are highly overexpressed in iAMP21 (17), none of these genes have yet been identified to be causally deregulated by the amplification. Besides overexpression of genes on chromosome 21 (cis-effect), many genes outside of chromosome 21 are overexpressed as well (17), opening up the possibility of an indirect leukemic effect of chromosome 21 amplification (trans-effect).…”

Section: Introductionmentioning

confidence: 99%

Integrating copy number data of 64 iAMP21 BCP-ALL patients narrows the common region of amplification to 1.57 Mb

Hormann

Hoogkamer²,

Boeree³

et al. 2023

Front. Oncol.

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Background and purposeIntrachromosomal amplification of chromosome 21 (iAMP21) is a rare subtype of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). It is unknown how iAMP21 contributes to leukaemia. The currently known commonly amplified region is 5.1 Mb.MethodsWe aimed to narrow down the common region of amplification by using high resolution techniques. Array comparative genomic hybridization (aCGH) was used to determine copy number aberrations, Affymetrix U133 Plus2 expression arrays were used to determine gene expression. Genome-wide expression correlations were evaluated using Globaltest.ResultsWe narrowed down the common region of amplification by combining copy number data from 12 iAMP21 cases with 52 cases from literature. The combined common region of amplification was 1.57 Mb, located from 36.07 to 37.64 Mb (GRCh38). This region is located telomeric from, but not including, RUNX1, which is the locus commonly used to diagnose iAMP21. This narrow region, which falls inside the Down Syndrome critical region, includes 13 genes of which the expression of eight genes was significantly upregulated compared with 143 non-iAMP21 B-other cases. Among these, transcriptional repressor RIPPLY3 (also known as DSCR6) was the highest overexpressed gene (fold change = 4.2, FDR < 0.001) and most strongly correlated (R = 0.58) with iAMP21-related genome-wide expression changes.DiscussionThe more precise definition of the common region of amplification could be beneficial in the diagnosis of iAMP21 based on copy number analysis from DNA sequencing or arrays as well as stimulate functional research into the role of the included genes in iAMP21 biology.

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“…Human DYRK1a gene locus amplification is associated with Down syndrome and B-ALL, and a role for DYRK1a in regulating B-ALL has also been suggested in a mouse model study. 20,40,41 Our analysis of a human pediatric ALL database revealed DYRK1a amplification or mRNA overexpression in 10.83% of total cases. Integration of DYRK1a inhibitor into the treatment of DYRK1a hi ALL population may improve the outcomes.…”

Section: Discussionmentioning

confidence: 88%

DYRK1a mediates BAFF-induced noncanonical NF-κB activation to promote autoimmunity and B-cell leukemogenesis

Xie

Jie

et al. 2021

Blood

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B cell-activating factor (BAFF) mediates B cell survival and, when deregulated, also contributes to autoimmune diseases and B cell malignancies. The mechanism connecting BAFF receptor (BAFFR) signal to downstream pathways and pathophysiological functions is not well understood. Here we identified DYRK1a as a kinase that responds to BAFF stimulation and mediates BAFF-induced B cell survival. B cell-specific DYRK1a deficiency causes peripheral B cell reduction and ameliorates autoimmunity in a mouse model of lupus. An unbiased screen identified DYRK1a as a protein that interacts with TRAF3, a ubiquitin ligase component mediating degradation of the noncanonical NF-kB-inducing kinase (NIK). DYRK1a phosphorylates TRAF3 at serine-29 to interfere with its function in mediating NIK degradation, thereby facilitating BAFF-induced NIK accumulation and noncanonical NF-kB activation. Interestingly, B cell acute lymphoblastic leukemia (B-ALL) cells express high levels of BAFFR and respond to BAFF for noncanonical NF-kB activation and survival in a DYRK1a-dependent manner. Furthermore, DYRK1a promotes a mouse model of B-ALL through activation of the noncanonical NF-kB pathway. These results establish DYRK1a as a critical BAFFR signaling mediator and provide novel insight into B-ALL pathogenesis.

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Overexpression of chromatin remodeling and tyrosine kinase genes in iAMP21-positive acute lymphoblastic leukemia

Cited by 8 publications

References 59 publications

Clinical application of whole transcriptome sequencing for the classification of patients with acute lymphoblastic leukemia

Clinical application of whole transcriptome sequencing for the classification of patients with acute lymphoblastic leukemia

Integrating copy number data of 64 iAMP21 BCP-ALL patients narrows the common region of amplification to 1.57 Mb

DYRK1a mediates BAFF-induced noncanonical NF-κB activation to promote autoimmunity and B-cell leukemogenesis

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