Identification of recurrent truncated <i><scp>DDX</scp>3X</i> mutations in chronic lymphocytic leukaemia

Ojha, Juhi; Secreto, Charla; Rabe, Kari G.; Dyke, Daniel L. Van; Kortüm, K. Martin; Slager, Susan L.; Shanafelt, Tait D.; Fonseca, Rafaël; Kay, Neil E.; Braggio, Esteban

doi:10.1111/bjh.13211

Cited by 50 publications

(50 citation statements)

References 14 publications

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“…1c). In support of our findings, our exploration of the literature actually revealed the existence of DDX3X mutations in some previously reported cases of NKTCL 19 , Burkitt's lymphoma 26 and chronic lymphocytic leukemia 27 .…”

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confidence: 90%

Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma

et al. 2015

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Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.

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confidence: 90%

Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma

et al. 2015

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“…Thus, full-length but inactive protein is selected by this tumor type. In contrast, in blood cancers such as natural-killer/T-cell lymphoma (17), Burkitt lymphoma (63), or chronic lymphocytic leukemia (15,16), DDX3X variants include nonsynonymous single nucleotide variants but also many premature stop codons, frameshifts, and splice variants. The elucidation of the minimal conserved functional core and the new, high-resolution structures of DDX3 presented here is of broad utility for molecular modeling and when predicting the function of truncating variants of DDX3 present in patient samples.…”

Section: Discussionmentioning

confidence: 99%

Autoinhibitory Interdomain Interactions and Subfamily-specific Extensions Redefine the Catalytic Core of the Human DEAD-box Protein DDX3

Floor

Condon

Sharma

et al. 2016

Journal of Biological Chemistry

112

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DEAD-box proteins utilize ATP to bind and remodel RNA and RNA-protein complexes. All DEAD-box proteins share a conserved core that consists of two RecA-like domains. The core is flanked by subfamily-specific extensions of idiosyncratic function. The Ded1/DDX3 subfamily of DEAD-box proteins is of particular interest as members function during protein translation, are essential for viability, and are frequently altered in human malignancies. Here, we define the function of the subfamily-specific extensions of the human DEAD-box protein DDX3. We describe the crystal structure of the subfamily-specific core of wild-type DDX3 at 2.2 Å resolution, alone and in the presence of AMP or nonhydrolyzable ATP. These structures illustrate a unique interdomain interaction between the two ATPase domains in which the C-terminal domain clashes with the RNA-binding surface. Destabilizing this interaction accelerates RNA duplex unwinding, suggesting that it is present in solution and inhibitory for catalysis. We use this core fragment of DDX3 to test the function of two recurrent medulloblastoma variants of DDX3 and find that both inactivate the protein in vitro and in vivo. Taken together, these results redefine the structural and functional core of the DDX3 subfamily of DEADbox proteins.DEAD-box proteins are ATP-dependent RNA-binding proteins that remodel RNA structures and RNA-protein complexes, stably clamp RNA, and promote fluidity within RNA granules (1-3). The human DEAD-box protein DDX3 (encoded by DDX3X) and its yeast ortholog Ded1p have been implicated in numerous functions including translation initiation (4 -12). Messenger RNA molecules containing especially long or structured 5Ј leader sequences are particularly sensitive to DDX3 activity (6,7,12,13). DDX3X is frequently mutated in numerous cancer types (5), such as chronic lymphocytic leukemia (14 -16), natural killer/T-cell lymphoma (17), head and neck squamous cell carcinoma (18,19), and lung cancer (20). DDX3X is also one of the most frequently mutated genes in the highly malignant brain tumor medulloblastoma (21-24). In medulloblastoma, many mutations are predicted to inactivate DDX3, and some have been demonstrated to diminish activities in vitro (17,25).DEAD-box proteins are defined by 12 different motifs that function in ATP binding or hydrolysis and RNA binding, or couple ATP and RNA binding (1). Outside of these conserved motifs, each DEAD-box protein subfamily has unique tails that lie N-or C-terminal to the helicase core and contain elements that define the unique properties of that subfamily. For example, DDX21 has a GUCT domain in its C-terminal extension (26, 27), DDX5 has tandem P68HR domains in its C-terminal extension, and DDX43 has a KH1 domain in its N-terminal extension. However, as the tails of each DEAD-box protein subfamily are idiosyncratic, whereas the cores are very similar (28,29), it is essential to study individual subfamilies of DEAD-box proteins in detail to understand the role of subfamily-specific tails.DDX3 is a member of the Ded1/DDX...

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“…DDX3X mutants in NK/T-cell lymphomas exhibited decreased RNA-unwinding activity, loss of suppressive effects on cellcycle progression and induce transcriptional activation of NF-jB and MAPK pathways [60]. A recent analysis suggested that CLL DDX3X mutations were associated with unmutated IGHV and poor outcome [61]. XPO1 participates to the nucleo-cytoplasmic export of proteins and RNA [62] and plays a role in CLL cell survival and resistance to treatment [63] (Fig.…”

Section: Mutations Of the Sf3b1 Gene And Rna Biologymentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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Identification of recurrent truncated DDX3X mutations in chronic lymphocytic leukaemia

Cited by 50 publications

References 14 publications

Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma

Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma

Autoinhibitory Interdomain Interactions and Subfamily-specific Extensions Redefine the Catalytic Core of the Human DEAD-box Protein DDX3

Chronic lymphocytic leukemia: Time to go past genomics?

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