Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

Zhou, Peixun; Blain, Alex; Newman, Alexander M.; Zaka, Masood; Chagaluka, George; Adlar, Filbert R.; Offor, Ugonna T.; Broadbent, Casey; Chaytor, Lewis; Whitehead, Amber; Hall, Amy B.; O’Connor, Hettie; Noorden, Susan Van; Lampert, Irvin A.; Bailey, Simon; Molyneux, Elizabeth; Bacon, Chris M.; Bomken, Simon; Rand, Vikki

doi:10.1182/bloodadvances.2018029546

Cited by 27 publications

(29 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, there is no evidence of a role of FOXO1-activating mutations in BL progression. The clinical outcome of BL does not depend on the FOXO1 mutational status and there is no increase in the frequency of FOXO1 mutations in relapsed cases [44]. This is in clear contrast to DLBCL in which FOXO1 mutations are associated with poor outcome [45,46] and their frequency strongly increases in refractory or relapsed cases [47].…”

Section: Discussionmentioning

confidence: 91%

“…EBV infection, which activates PI3K-AKT signalling, indicates a role of PI3K-AKT activation at early stages, but the establishing of BL apparently requires repression of the EBV programme, including PI3K-AKT-and NF-κB-activating LMP genes [8,14,48]. This view is supported by the observation that FOXO1 mutations are found at a significantly higher frequency in endemic BL cases compared with sporadic BL [44]. Thus, frequent FOXO1activating mutations, which confer resistance to the AKTdependent inactivation, might be remnants of the adaptive response to the initial transitory PI3K-AKT activation.…”

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma

et al. 2019

View full text Add to dashboard Cite

In addition to oncogenic MYC translocations, Burkitt lymphoma (BL) depends on the germinal centre (GC) dark zone (DZ) B cell survival and proliferation programme, which is characterized by relatively low PI3K-AKT activity. Paradoxically, PI3K-AKT activation facilitates MYC-driven lymphomagenesis in mice, and it has been proposed that PI3K-AKT activation is essential for BL. Here we show that the PI3K-AKT activity in primary BLs and BL cell lines does not exceed that of human non-neoplastic tonsillar GC DZ B cells. BLs were not sensitive to AKT1 knockdown, which induced massive cell death in pAKT high DLBCL cell lines. Likewise, BL cell lines show low sensitivity to pan-AKT inhibitors. Moreover, hyperactivation of the PI3K-AKT pathway by overexpression of a constitutively active version of AKT (myrAKT) or knockdown of PTEN repressed the growth of BL cell lines. This was associated with increased AKT phosphorylation, NF-κB activation, and downregulation of DZ genes including the proto-oncogene MYB and the DZ marker CXCR4. In contrast to GCB-DLBCL, PTEN overexpression was tolerated by BL cell lines. We conclude that the molecular mechanisms instrumental to guarantee the survival of normal DZ B cells, including the tight regulation of the PTEN-PI3K-AKT axis, also operate in the survival/proliferation of BL.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 95%

Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Additionally, an earlier study using tissue samples from 25 Japanese NKTCL patients identified that 3 cases had mutations in the DDX3X gene by conventional Sanger sequencing 21 , while another study in China showed recurrent loss-of-function mutations in DDX3X in 21 out of 105 NKTCL subjects by NGS 11 . In a UK cohort of 78 sporadic BL cases, 15 DDX3X mutations (6 nonsense and 9 missense) were detected, and all but 1 DDX3X mutations were localized in either the DEAD box helicase domain or the helicase C terminus 22 . However, the clinical significance of these lesions remains unclear in most cases.…”

Section: Discussionmentioning

confidence: 99%

“…Available database in the International Cancer Genome Consortium (ICGC) 18 and the Catalogue of Somatic Mutations in Cancer (COSMIC) 19 portals showed mutations in DDX3X in 63 out of 1319 (4.7%) and 160 out of (3.1%) DLBCL cases, respectively. In addition, several other reports that were not in the above databases also demonstrated DDX3X mutations in NHL [8][9][10][11][20][21][22][23][24][25][26][27][28][29][30][31][32][33] . Altogether, we identified 165 missense, 81 truncating, and 3 in-frame indel mutational variants in the DDX3X gene in NHL (Fig.…”

Section: Recurrent Ddx3x Mutations In Nhl Are Associated With Worse Cmentioning

confidence: 99%

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

Kizhakeyil

Zaini

Poh

et al. 2021

Preprint

View full text Add to dashboard Cite

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.

show abstract

“…Surprisingly, FOXO1 knockdown in the MYC-PI3K driven mouse model of BL resulted in cell death and growth arrest [9]. Moreover, FOXO1 gene editing results in time-dependent selection of in-frame edited clones [9] and impedes proliferation of BL cell lines [19], indicating a role of FOXO1 in BL lymphomagenesis.…”

Section: Introductionmentioning

confidence: 99%

FOXO1 Confers Maintenance of the Dark Zone Proliferation and Survival Program and Can Be Pharmacologically Targeted in Burkitt Lymphoma

Gehringer

Weissinger

Swier

et al. 2019

Cancers

View full text Add to dashboard Cite

The FOXO1 transcription factor plays a central role in the proliferation and survival of B cells at several stages of differentiation. B cell malignancies, with exception of classical Hodgkin lymphoma, maintain expression of FOXO1 at levels characteristic for their non-malignant counterparts. Extensive expression profiling had revealed that Burkitt lymphoma (BL) show many characteristics of the dark zone (DZ) germinal center (GC) B cell program. Here we show that FOXO1 knockdown inhibits proliferation of human BL cell lines. The anti-proliferative effect of the FOXO1 knockdown is associated with the repression of the DZ B cell program including expression of MYB, CCND3, RAG2, BACH2, and CXCR4. In addition, the induction of signaling pathways of the light zone (LZ) program like NF-κB and PI3K-AKT was observed. Using a rescue experiment we identified downregulation of the proto-oncogene MYB as a critical factor contributing to the antiproliferative effect of FOXO1 knockdown. In an attempt to estimate the feasibility of pharmacological FOXO1 repression, we found that the small molecular weight FOXO1 inhibitor AS1842856 induces cell death and growth arrest in BL cell lines at low concentrations. Interestingly, we found that overactivation of FOXO1 also induces growth inhibition in BL cell lines, indicating the importance of a tight regulation of FOXO1 activity in BL.

show abstract

Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

Cited by 27 publications

References 43 publications

Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma

Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma

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

FOXO1 Confers Maintenance of the Dark Zone Proliferation and Survival Program and Can Be Pharmacologically Targeted in Burkitt Lymphoma

Contact Info

Product

Resources

About