To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi).
In a French cancer center, we identified and described the ...profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort.
From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS.
In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.
The discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family that signals in response to collagen and that has been implicated in cancer progression. In the present ...study, we investigated the expression and role of DDR1 in human melanoma progression. Immunohistochemical staining of human melanoma specimens (n = 52) shows high DDR1 expression in melanoma lesions that correlates with poor prognosis. DDR1 expression was associated with the clinical characteristics of Clark level and ulceration and with BRAF mutations. Downregulation of DDR1 by small interfering RNA (siRNA) in vitro inhibited melanoma cells malignant properties, migration, invasion, and survival in several human melanoma cell lines. A DDR tyrosine kinase inhibitor (DDR1‐IN‐1) significantly inhibited melanoma cell proliferation in vitro, and ex vivo and in tumor xenografts, underlining the promising potential of DDR1 inhibition in melanoma.
Adult human mesenchymal stromal cells (hMSCs) have the potential to differentiate into chondrogenic, adipogenic, or osteogenic lineages, providing a potential source for tissue regeneration. An ...important issue for efficient bone regeneration is to identify factors that can be targeted to promote the osteogenic potential of hMSCs. Using transcriptome analysis, we found that integrin α5 (ITGA5) expression is up-regulated during dexamethasone-induced osteoblast differentiation of hMSCs. Gain-of-function studies showed that ITGA5 promotes the expression of osteoblast phenotypic markers and in vitro osteogenesis of hMSCs. Down-regulation of endogenous ITGA5 using specific shRNAs blunted osteoblast marker gene expression and osteogenic differentiation. Molecular analyses showed that the enhanced osteoblast differentiation induced by ITGA5 was mediated by activation of focal adhesion kinase/ERK1/2-MAPKs and PI3K signaling pathways. Remarkably, activation of endogenous ITGA5 using agonists such as a specific antibody that primes the integrin or a peptide that specifically activates ITGA5 was sufficient to enhance ERK1/2-MAPKs and PI3K signaling and to promote osteoblast differentiation and osteogenic capacity of hMSCs. Importantly, we demonstrated that hMSCs engineered to overexpress ITGA5 exhibited a marked increase in their osteogenic potential in vivo. Taken together, these findings not only reveal that ITGA5 is required for osteoblast differentiation of adult hMSCs but also provide a targeted strategy using ITGA5 agonists to promote the osteogenic capacity of hMSCs. This may be used for tissue regeneration in bone disorders where the recruitment or capacity of hMSCs is compromised.
Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic ...anemia (n = 20), MDS (n = 18), AML (n = 11), or no BM abnormality (n = 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), −7/7q (17.2%), and 11q− (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBPα mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q+, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure.
PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the ...frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.
Under environmental stress, previously hidden additive genetic variation can be unmasked and exposed to selection. The amount of hidden variation is expected to be higher for life history traits, ...which strongly correlate to individual fitness, than for morphological traits, in which fitness effects are more ambiguous. However, no consensual pattern has been recovered yet, and this idea is still debated in the literature. Here, we hypothesize that the classical categorization of traits (i.e., life history and morphology) may fail to capture their proximity to fitness. In the desert locust, Schistocerca gregaria, a model organism for the study of insect polyphenism, we quantified changes in additive genetic variation elicited by lifetime thermal stress for ten traits, in which evolutionary significance is known. Irrespective of their category, traits under strong stabilizing selection showed genetic invariance with environmental stress, while traits more loosely associated with fitness showed a marked increase in additive genetic variation in the stressful environment. Furthermore, traits involved in adaptive phenotypic plasticity (growth compensation) showed either no change in additive genetic variance or a change of moderate magnitude across thermal environments. We interpret this mitigated response of plastic traits in the context of integrated evolution to adjust the entire phenotype in heterogeneous environments (i.e., adaptiveness of initial plasticity, compromise of phenotypic compensation with stress, and shared developmental pathway). Altogether, our results indicate, in agreement with theoretical expectations, that environmental stress can increase available additive genetic variance in some desert locust traits, but those closely linked to fitness are largely unaffected. Our study also highlights the importance of assessing the proximity to fitness of a trait on a case‐by‐case basis and in an ecologically relevant context, as well as considering the processes of canalization and plasticity, involved in the control of phenotypic variation.
The idea that environmental stress can unmask cryptic additive genetic variation and expose it to selection is well accepted. Still, no consensus has been reached on the potential magnitude of these stress‐induced changes. In the desert locust (Schistocerca gregaria), we show that ecologically relevant environmental stress increases available additive genetic variance only for traits that are not directly linked to individual fitness. Our results suggest that using a life history versus morphology categorization of traits as a proxy for their link to fitness might be too simplistic, and instead, traits' proximity to fitness should be known specifically in the studied populations. Our study also highlights that traits' control of phenotypic variation (canalization vs. plasticity) should not be overlooked.
The aim of our study was to analyze the factors contributing to heterogeneity of prognosis in patients with hyperdiploidy>50 chromosomes (HD>50), a group of B-cell precursor acute lymphoblastic ...leukemia with favorable outcome. The 541 HD>50 patients registered prospectively in the 58951 European Organisation for Research and Treatment of Cancer (EORTC) Children's Leukemia Group (CLG) trial, identified by karyotype (446 patients) and by DNA index (DI) (490 patients), had a 6-year event-free survival (EFS) of 89.0% (standard error SE = 1.5%) and a 6-year overall survival (OS) of 95.9% (SE = 0.9%). The strongest prognostic factor was the modal number of chromosomes (MNC): the 6-year EFS of 51-53, 54-57, and 58-66 MNC groups were 80%, 89%, and 99%, respectively (P < .0001). Ploidy assessed by DI was also a favorable factor: the higher the DI, the better the outcome. The 6-year EFS of the 3 subgroups of DI < 1.16/≥1.16-<1.24/≥1.24 were 83%, 90%, and 95%, respectively (P = .009). All usual combinations of trisomies (chromosomes 4, 10, 17, 18) were significant favorable factors but had lower EFS when MNC was lower than 58. In multivariate analysis, MNC remained the strongest factor. Consequently, the best indicator for excellent outcome was ploidy assessed by karyotype because patients with 58-66 chromosomes stood every chance of being cured (OS of 100% at 6-year follow-up) with less-intensive therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728. Registered: http://www.eortc.org/, http://clinicaltrials.gov/show/NCT00003728.
•Patients with 58-66 chromosomes have 99% event-free survival and 100% overall survival in the 58951 EORTC-CLG study.•The higher the ploidy, the better the prognosis in the 58951 EORTC-CLG study.
Between plagues, the solitarious desert locust (Schistocerca gregaria) is generally thought to exist as small populations, which are particularly prone to extinction events in arid regions of Africa ...and Asia. Given the high genetic structuring observed in one geographical area (the Eritrean coast) by former authors, a metapopulation dynamics model involving repeated extinction and colonization events was favoured. In this study, we assessed the validity of a demographic scenario involving temporary populations of the solitarious phase of the desert locust by analysing large‐scale population genetic data. We scored 24 microsatellites in 23 solitarious population samples collected over most of the species range during remission. We found very little genetic structuring and little evidence of declining genetic diversity. A Bayesian clustering method distinguished four genetically differentiated units. Three groups were largely consistent with three population samples which had undergone recent bottleneck events. Nevertheless, the last genetically homogeneous unit included all individuals from the remaining 18 population samples and did not show evidence of demographic disequilibrium. An approximate Bayesian computation treatment indicated a large population size for this main genetic group, moderately reduced between plague and remission but still containing tens of thousands of individuals. Our results diverge from the hypothesis of a classical metapopulation dynamics model. They instead support the scenario in which large populations persist in the solitarious phase of the desert locust.
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