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Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia.

ABSTRACT: Genomic studies have recently identified RPS15 as a new driver gene in aggressive and chemorefractory cases of chronic lymphocytic leukemia (CLL). RPS15 encodes a ribosomal protein whose conserved C-terminal domain extends into the decoding center of the ribosome. We demonstrate that mutations in highly conserved residues of this domain affect protein stability, by increasing its ubiquitin-mediated degradation, and cell-proliferation rates. On the other hand, we show that mutated RPS15 can be loaded into the ribosomes, directly impacting on global protein synthesis and/or translational fidelity in a mutation-specific manner. Quantitative mass spectrometry analyses suggest that RPS15 variants may induce additional alterations in the translational machinery, as well as a metabolic shift at the proteome level in HEK293T and MEC-1 cells. These results indicate that CLL-related RPS15 mutations might act following patterns known for other ribosomal diseases, likely switching from a hypo- to a hyperproliferative phenotype driven by mutated ribosomes. In this scenario, loss of translational fidelity causing altered cell proteostasis can be proposed as a new molecular mechanism involved in CLL pathobiology.

SUBMITTER: Bretones G

PROVIDER: S-EPMC6410914 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia

Project description:Genomic studies have recently identified RPS15 as a new driver gene in aggressive and chemorefractory cases of chronic lymphocytic leukemia (CLL). RPS15 encodes a ribosomal protein whose conserved C-terminal domain extends into the decoding center of the ribosome. We demonstrate that mutations in highly conserved residues of this domain affect both protein stability —by increasing its ubiquitin-mediated degradation— and cell proliferation rates. On the other hand, we show that mutated RPS15 can be loaded into the ribosomes, directly impacting on global protein synthesis and/or translational fidelity in a mutation-specific manner. Quantitative mass-spectrometry analyses suggest that RPS15 variants may induce additional alterations in the translational machinery as well as a metabolic shift at the proteome level in both HEK293T and MEC-1 cells. These results indicate that CLL-related RPS15 mutations might act following patterns known for other ribosomal diseases, likely switching from a hypo- to a hyperproliferative phenotype driven by mutated ribosomes. In this scenario, loss of translational fidelity causing altered cell proteostasis can be proposed as a new molecular mechanism involved in CLL pathobiology.

2019-09-09 | PXD010924 | Pride

RPS15 mutations rewire RNA translation in chronic lymphocytic leukemia.

Project description:Recent studies of chronic lymphocytic leukemia (CLL) have reported recurrent mutations in the RPS15 gene, which encodes the ribosomal protein S15 (RPS15), a component of the 40S ribosomal subunit. Despite some evidence about the role of mutant RPS15 (mostly obtained from the analysis of cell lines), the precise impact of RPS15 mutations on the translational program in primary CLL cells remains largely unexplored. Here, using RNA sequencing and ribosome profiling, a technique that involves measuring translational efficiency, we sought to obtain global insight into changes in translation induced by RPS15 mutations in CLL cells. To this end, we evaluated primary CLL cells from patients with wild-type or mutant RPS15 as well as MEC1 CLL cells transfected with mutant or wild-type RPS15. Our data indicate that RPS15 mutations rewire the translation program of primary CLL cells by reducing their translational efficiency, an effect not seen in MEC1 cells. In detail, RPS15 mutant primary CLL cells displayed altered translation efficiency of other ribosomal proteins and regulatory elements that affect key cell processes, such as the translational machinery and immune signaling, as well as genes known to be implicated in CLL, hence highlighting a relevant role for RPS15 in the natural history of CLL.

| S-EPMC8288675 | biostudies-literature

Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia.

Project description:TP53 mutations are strong predictors of poor survival and refractoriness in chronic lymphocytic leukemia (CLL) and have direct implications for disease management. Clinical information on TP53 mutations is limited to lesions represented in >20% leukemic cells. Here, we tested the clinical impact and prediction of chemorefractoriness of very small TP53 mutated subclones. The TP53 gene underwent ultra-deep-next generation sequencing (NGS) in 309 newly diagnosed CLL. A robust bioinformatic algorithm was established for the highly sensitive detection of few TP53 mutated cells (down to 3 out of ∼1000 wild-type cells). Minor subclones were validated by independent approaches. Ultra-deep-NGS identified small TP53 mutated subclones in 28/309 (9%) untreated CLL that, due to their very low abundance (median allele frequency: 2.1%), were missed by Sanger sequencing. Patients harboring small TP53 mutated subclones showed the same clinical phenotype and poor survival (hazard ratio = 2.01; P = .0250) as those of patients carrying clonal TP53 lesions. By longitudinal analysis, small TP53 mutated subclones identified before treatment became the predominant population at the time of CLL relapse and anticipated the development of chemorefractoriness. This study provides a proof-of-principle that very minor leukemia subclones detected at diagnosis are an important driver of the subsequent disease course.

| S-EPMC4017291 | biostudies-literature

Altered T Follicular Helper Cell Subsets and Function in Chronic Lymphocytic Leukemia.

Project description:Follicular helper T cells (TFH) have specialized properties in promoting normal B cell activation but their role in chronic lymphocytic leukemia (CLL) is unknown. We find that TFH cells are elevated in CLL patients and are phenotypically abnormal, expressing higher levels of PD-1, TIGIT, CD40L, IFNγ and IL-21, and exhibiting abnormal composition of TFH1, TFH2 and TFH17 subsets. Frequencies of CD4-positive T cells expressing TFH1 markers and IL-21 were positively correlated with patient lymphocyte counts and RAI stage, suggesting that accumulation of abnormal TFH cells is concomitant with expansion of the leukemic B cell clone. Treatment with ibrutinib led to normalization of TFH frequencies and phenotype. TFH cells identified in CLL bone marrow display elevated expression of several functional markers compared to blood TFH cells. CLL T cell-B cell co-culture experiments revealed a correlation of patient TFH frequencies with functional ability of their CD4-positive T cells to promote CLL proliferation. Conversely, CLL cells can preferentially activate the TFH cell subset in co-culture. Together our results indicate that CLL development is associated with expansion of abnormal TFH populations that produce elevated levels of cytokines and costimulatory molecules which may help support CLL proliferation.

| S-EPMC8113764 | biostudies-literature

Innate lymphoid cells are expanded and functionally altered in chronic lymphocytic leukemia.

Project description: Not available

| S-EPMC5394863 | biostudies-literature

A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi.

Project description:B cell chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is a clonal expansion of CD5(+)CD19(+) B lymphocytes. Two types of CLLs are being distinguished as carrying either unmutated or somatically mutated immunoglobulins (Igs), which are associated with unfavorable and favorable prognoses, respectively. More than 30% of CLLs can be grouped based on their expression of stereotypic B cell receptors (BCRs), strongly suggesting that distinctive antigens are involved in the development of CLL. Unmutated CLLs, carrying Ig heavy chain variable (IGHV) genes in germline configuration, express low-affinity, poly-, and self-reactive BCRs. However, the antigenic specificity of CLLs with mutated IGHV-genes (M-CLL) remained elusive. In this study, we describe a new subset of M-CLL, expressing stereotypic BCRs highly specific for ?-(1,6)-glucan, a major antigenic determinant of yeasts and filamentous fungi. ?-(1,6)-glucan binding depended on both the stereotypic Ig heavy and light chains, as well as on a distinct amino acid in the IGHV-CDR3. Reversion of IGHV mutations to germline configuration reduced the affinity for ?-(1,6)-glucan, indicating that these BCRs are indeed affinity-selected for their cognate antigen. Moreover, CLL cells expressing these stereotypic receptors proliferate in response to ?-(1,6)-glucan. This study establishes a class of common pathogens as functional ligands for a subset of somatically mutated human B cell lymphomas.

| S-EPMC3549718 | biostudies-literature

Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia.

Project description:An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one 'sub-Sanger' TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as β2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring.

| S-EPMC4558590 | biostudies-literature

Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium.

Project description:PurposeLenalidomide is an immunomodulatory agent with therapeutic activity in chronic lymphocytic leukemia (CLL). In preclinical models, lenalidomide acted synergistically with rituximab. The CLL Research Consortium initiated a phase II study to evaluate this combination in treatment-naive patients.Patients and methodsLenalidomide was initiated at 2.5 mg/day and was escalated based on treatment tolerability to a maximum of 10 mg/day, for 21 days/cycle, for a maximum of seven cycles. Rituximab was administered at the end of cycle 1 and was continued for seven cycles. Patients received allopurinol and aspirin for prophylaxis.ResultsSixty-nine patients enrolled onto one of two age-specific strata; patients' median age was 56 and 70 years for arms A and B, respectively. Patients in the older-patient stratum more frequently had elevated serum beta-2 microglobulin levels, high-risk Rai stage, and were less likely to complete the maximum planned therapy. Adverse events were similar in the two arms. Nonhematologic toxicity was predominantly at grade 1/2, and neutropenia was the most common hematologic adverse event. The response rate for arm A was 95%, with 20% complete responses (CRs) and 20% nodular partial responses. Of arm B patients, 78% achieved a response, of which 11% were CRs. Median progression-free survival (PFS) was 19 months for the younger cohort and 20 months for the older cohort.ConclusionIntrapatient dose-escalation was safe. The majority of patients reached the maximum lenalidomide dose and experienced a response to a defined seven-cycle course of lenalidomide and rituximab therapy. Despite differences in baseline characteristics and the response rate between the two strata, the PFS did not differ.

| S-EPMC4067945 | biostudies-literature

Acrocyanosis revealing chronic lymphocytic leukemia.

Project description:Cold agglutinin disease arising in the context of chronic lymphocytic leukemia can misdiagnose a warm autoimmune hemolytic anemia.

| S-EPMC4831394 | biostudies-other

Normal serum protein electrophoresis and mutated IGHV genes detect very slowly evolving chronic lymphocytic leukemia patients.

Project description:More than 35 years after the Binet classification, there is still a need for simple prognostic markers in chronic lymphocytic leukemia (CLL). Here, we studied the treatment-free survival (TFS) impact of normal serum protein electrophoresis (SPE) at diagnosis. One hundred twelve patients with CLL were analyzed. The main prognostic factors (Binet stage; lymphocytosis; IGHV mutation status; TP53, SF3B1, NOTCH1, and BIRC3 mutations; and cytogenetic abnormalities) were studied. The frequencies of IGHV mutation status, cytogenetic abnormalities, and TP53, SF3B1, NOTCH1, and BIRC3 mutations were not significantly different between normal and abnormal SPE. Normal SPE was associated with Binet stage A, nonprogressive disease for 6 months, lymphocytosis below 30 G/L, and the absence of the IGHV3-21 gene rearrangement which is associated with poor prognosis. The TFS of patients with normal SPE was significantly longer than that of patients with abnormal SPE (log-rank test: P = 0.0015, with 51% untreated patients at 5.6 years and a perfect plateau afterward vs. a median TFS at 2.64 years for abnormal SPE with no plateau). Multivariate analysis using two different Cox models and bootstrapping showed that normal SPE was an independent good prognostic marker for either Binet stage, lymphocytosis, or IGHV mutation status. TFS was further increased when both normal SPE and mutated IGHV were present (log-rank test: P = 0.008, median not reached, plateau at 5.6 years and 66% untreated patients). A comparison with other prognostic markers suggested that normal SPE could reflect slowly advancing CLL disease. Altogether, our results show that a combination of normal SPE and mutated IGHV genes defines a subgroup of patients with CLL who evolve very slowly and who might never need treatment.

| S-EPMC6010869 | biostudies-other

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