Sequential Inverse Dysregulation of the RNA Helicases DDX3X and DDX3Y Facilitates MYC-Driven Lymphomagenesis

Gong, Chun; Krupka, Joanna A.; Gao, Jie; Grigoropoulos, Nicholas F.; Screen, Michael; Usheva, Zelvera; Cucco, Francesco; Barrans, Sharon; Painter, Daniel; Mohammed, Mahirah; Häupl, Björn; Bornelöv, Susanne; Mozos, Igor Ruiz de los; Wang, Meng; Zhou, Peixun; Blain, Alex; Forde, Sorcha; Matthews, Jamie; Tan, Meiling; Burke, G.A. Amos; Sze, Siu Kwan; Beer, Philip; Combes, Burton; Campbell, Peter J.; Rand, Vikki; Turner, Suzanne; Ule, Jernej; Roman, Eve; Tooze, Reuben; Oellerich, Thomas; Turner, Martin; Du, Ming‐Qing; Samarajiwa, Shamith; Hodson, Daniel

doi:10.2139/ssrn.3520953

Cited by 9 publications

(16 citation statements)

References 116 publications

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“…Second, the two paralogs could have the same target propensity but distinct subcellular localizations, and thus differ in their effects. These possibilities are partially rebuffed by the gain of DDX3Y expression complementing for loss of DDX3X in certain lymphoid malignancies (Gong et al, 2020) and in BHK21 hamster cells (Sekiguchi et al, 2004). Additionally, a genome-wide CRISPR screen for essential genes identified DDX3Y as being essential only in Raji cells (which are also of hematopoietic origin), which had suffered a truncating mutation in DDX3X, further indicating genetic complementation (Wang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…DDX3X escapes X-inactivation in a wide range of tissues (Cotton et al, 2015). Mutations in DDX3X are associated with numerous pathologies, including cancers like medulloblastoma (Floor et al, 2016; Kool et al, 2014; Oh et al, 2016), chronic lymphocytic leukemia (Ojha et al, 2015), squamous cell carcinoma (Stransky et al, 2011), Burkitt’s lymphoma (Gong et al, 2020), and many others (Sharma and Jankowsky, 2014). Heterozygous missense or loss-of-function mutations in DDX3X are also implicated in intellectual disability and autism-spectrum disorders in females (Iossifov et al, 2014; Lennox et al, 2020; Ruzzo et al, 2019; Scala et al, 2019; Snijders Blok et al, 2015; Takata et al, 2018; Wang et al, 2018; Yuen et al, 2017), with the severity of phenotype correlating with the degree of reduction in DDX3X catalytic activity (Lennox et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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DDX3X and DDX3Y are redundant in protein synthesis

Venkataramanan

Wilkins

Floor

2020

Preprint

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DDX3 is a DEAD-box RNA helicase that regulates translation and is encoded by the X- and Y-linked paralogs DDX3X and DDX3Y. While DDX3X is ubiquitously expressed in human tissues and essential for viability, DDX3Y is male-specific and shows lower and more variable expression than DDX3X in somatic tissues. Heterozygous genetic lesions in DDX3X mediate a class of developmental disorders called DDX3X syndrome, while loss of DDX3Y is implicated in male infertility. One possible explanation for female-bias in DDX3X syndrome is that DDX3Y encodes a polypeptide with different biochemical activity. In this study, we use ribosome profiling and in vitro translation to demonstrate that the X- and Y-linked paralogs of DDX3 play functionally redundant roles in translation. We find that transcripts that are sensitive to DDX3X depletion or mutation are rescued by complementation with DDX3Y. Our data indicate that DDX3X and DDX3Y proteins can functionally complement each other in human cells. DDX3Y is not expressed in a large fraction of the central nervous system. These findings suggest that expression differences, not differences in paralog-dependent protein synthesis, underlie the sex-bias of DDX3X-associated diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DDX3X and DDX3Y are redundant in protein synthesis

Venkataramanan

Wilkins

Floor

2020

Preprint

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“…Genomic lesions in DDX3X have been detected by our group and others in various haematologic malignancies, including NKTCL 11,24 , DLBCL 9,25,26 , hairy cell leukaemia 27 , CLL 28 , acute lymphoblastic leukaemia (ALL) 49 and BL 50 . For example, a multiplatform genomic analysis of 574 unclassified DLBCL biopsy samples identifying 19 missense, 7 truncating and 1 in-frame mutations 8 .…”

Section: Discussionmentioning

confidence: 78%

“…One of the main limitations of our survival analysis is the retrospective nature of the cBioPortal cohort and our consequent inability to perform a multivariable analysis to confirm if DDX3X mutations are independent predictors of poor survival. Indeed, data are emerging that DDX3X loss-of-function may synergize with MYC overexpression during early lymphomagenesis 50 . Our demonstration of increased resistance to doxorubicin and retained sensitivity to STAT3 inhibition in DDX3X-mutated/depleted cells argues for an independent influence of DDX3X on cancer drug response.…”

Section: Discussionmentioning

confidence: 99%

“…These cells were subsequently serum starved for 48 h and then treated with doxycycline (100 ng/mL) for additional 48 h to induce knockdown and then analysed. Methodologies for the CRISPR knock-in of the R475C DDX3X variant have been described earlier 50 . Briefly, sgRNAs for R475C and a silent mutation were spliced into the Cas9 plasmid pSpCas9(BB)-2A-GFP (PX458, Addgene, RRID: Addgene_48138) and electroporated into U2932 cells using the Amaxa Nucleofector platform.…”

Section: Rnai-mediated Depletion Of Ddx3x and R475c Crispr Knock-in Imentioning

confidence: 99%

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DDX3X Loss is Associated with Aggressive Phenotypes in Non-Hodgkin’s Lymphomas

Kizhakeyil

Zaini

Poh

et al. 2021

Preprint

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Non-Hodgkin’s lymphoma (NHL) is a diverse group of malignancies, encompassing the most common diffuse large B-cell lymphoma (DLBCL) to the rarer T-cell lymphomas. DDX3X is an RNA helicase and, depending on tumour type, plays tumour suppressive or oncogenic roles in cancer. However, its role in NHL is not clear. Targeted sequencing of DDX3X hotspots on exons 8-15 in a cohort of 158 unselected DLBCL subjects showed DDX3X mutations in 5 cases; whereas whole exome sequencing in a cohort of 9 relapsed/refractory DLBCL patients treated with R-CHOP identified DDX3X mutations in 4 cases. DLBCL patients (n=223) with DDX3X mutations had worse 5-year overall survival (22%) compared to patients with wild-type DDX3X (72%, p=0.021). Using DLBCL and cutaneous T-cell lymphoma (CTCL) cell lines, we showed that the expression of mutant DDX3X-R475C or DDX3X knockdown significantly enhanced cell migratory/invasive potential and elevated the phosphorylation of STAT3, Akt and p42/44. DDX3X loss increased resistance to doxorubicin and histone deacetylase targeting drugs in DLBCL and CTCL cells, respectively. Importantly, B- and T-cell lineage DDX3X-depleted cells remained sensitive to STAT3 inhibition. We conclude that DDX3X mutations are important driver lesions in NHL subtypes and are associated with chemoresistance but may be countered with a STAT3 inhibitor.

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Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age

et al. 2022

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While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.

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Sequential Inverse Dysregulation of the RNA Helicases DDX3X and DDX3Y Facilitates MYC-Driven Lymphomagenesis

Cited by 9 publications

References 116 publications

DDX3X and DDX3Y are redundant in protein synthesis

DDX3X and DDX3Y are redundant in protein synthesis

DDX3X Loss is Associated with Aggressive Phenotypes in Non-Hodgkin’s Lymphomas

Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age

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