De Santis Sara
@unibo.it
Alma Mater Studiorum Università di Bologna
University of Bologna
RESEARCH INTERESTS
Hematology
Scopus Publications
Scopus Publications
Adela Benesova, Sara De Santis, Vaclava Polivkova, Pavla Pecherkova, Jitka Krizkova, Pavla Suchankova, Cecilia Monaldi, Hana Klamova, Dana Srbova, Hana Zizkova,et al.
Wiley
Manuela Mancini, Cecilia Monaldi, Sara De Santis, Cristina Papayannidis, Michela Rondoni, Chiara Sartor, Samantha Bruno, Livio Pagano, Marianna Criscuolo, Roberta Zanotti,et al.
Springer Science and Business Media LLC
Abstract Background The SETD2 tumor suppressor gene encodes a histone methyltransferase that safeguards transcription fidelity and genomic integrity via trimethylation of histone H3 lysine 36 (H3K36Me3). SETD2 loss of function has been observed in solid and hematologic malignancies. We have recently reported that most patients with advanced systemic mastocytosis (AdvSM) and some with indolent or smoldering SM display H3K36Me3 deficiency as a result of a reversible loss of SETD2 due to reduced protein stability. Methods Experiments were conducted in SETD2-proficient (ROSAKIT D816V) and -deficient (HMC-1.2) cell lines and in primary cells from patients with various SM subtypes. A short interfering RNA approach was used to silence SETD2 (in ROSAKIT D816V cells), MDM2 and AURKA (in HMC-1.2 cells). Protein expression and post-translational modifications were assessed by WB and immunoblotting. Protein interactions were tested by using co-immunoprecipitation. Apoptotic cell death was evaluated by flow cytometry after annexin V and propidium iodide staining, respectively. Drug cytotoxicity in in vitro experiments was evaluated by clonogenic assays. Results Here, we show that the proteasome inhibitors suppress cell growth and induce apoptosis in neoplastic mast cells by promoting SETD2/H3K36Me3 re-expression. Moreover, we found that Aurora kinase A and MDM2 are implicated in SETD2 loss of function in AdvSM. In line with this observation, direct or indirect targeting of Aurora kinase A with alisertib or volasertib induced reduction of clonogenic potential and apoptosis in human mast cell lines and primary neoplastic cells from patients with AdvSM. Efficacy of Aurora A or proteasome inhibitors was comparable to that of the KIT inhibitor avapritinib. Moreover, combination of alisertib (Aurora A inhibitor) or bortezomib (proteasome inhibitor) with avapritinib allowed to use lower doses of each drug to achieve comparable cytotoxic effects. Conclusions Our mechanistic insights into SETD2 non-genomic loss of function in AdvSM highlight the potential value of novel therapeutic targets and agents for the treatment of patients who fail or do not tolerate midostaurin or avapritinib.
Miriam Iezza, Sofia Cortesi, Emanuela Ottaviani, Manuela Mancini, Claudia Venturi, Cecilia Monaldi, Sara De Santis, Nicoletta Testoni, Simona Soverini, Gianantonio Rosti,et al.
MDPI AG
The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at “high-risk”. Beyond the onset, a re-evaluation of the risk status is mandatory, monitoring the response to TKI treatment. Moreover, novel critical insights are emerging into the role of genomic factors, present at diagnosis or evolving on therapy. This review presents the current knowledge regarding prognostic factors in CML and their potential role for an improved risk classification and a subsequent enhancement of therapeutic decisions and disease management.
Cecilia Monaldi, Sara de Santis, Manuela Mancini, Cristina Papayannidis, Chiara Sartor, Michela Rondoni, Samantha Bruno, Michele Cavo, and Simona Soverini
Elsevier BV
Sara de Santis, Cecilia Monaldi, Margherita Martelli, Manuela Mancini, Samantha Bruno, Fausto Castagnetti, Gabriele Gugliotta, Katerina Machova Polakova, Thomas Ernst, Dianna Maar,et al.
Elsevier BV
Simona Soverini, Sara De Santis, Margherita Martelli, Cecilia Monaldi, Fausto Castagnetti, Gabriele Gugliotta, Cristina Papayannidis, Manuela Mancini, Samantha Bruno, Claudia Venturi,et al.
Springer Science and Business Media LLC
Manuela Mancini, Sara De Santis, Cecilia Monaldi, Fausto Castagnetti, Annalisa Lonetti, Samantha Bruno, Elisa Dan, Barbara Sinigaglia, Gianantonio Rosti, Michele Cavo,et al.
Frontiers Media SA
In chronic myeloid leukemia (CML), Aurora kinase A and Polo like kinase 1 (PLK1), two serine-threonine kinases involved in the maintenance of genomic stability by preserving a functional G2/M checkpoint, have been implicated in BCR::ABL1-independent resistance to the tyrosine kinase inhibitor (TKI) imatinib mesylate and in leukemic stem cell (LSC) persistence. It can be speculated that the observed deregulated activity of Aurora A and Plk1 enhances DNA damage, promoting the occurrence of additional genomic alterations contributing to TKI resistance and ultimately driving progression from chronic phase to blast crisis (BC). In this study, we propose a new therapeutic strategy based on the combination of Aurora kinase A or PLK1 inhibition with danusertib or volasertib, respectively, and WEE1 inhibition with AZD1775. Danusertib and volasertib used as single drugs induced apoptosis and G2/M-phase arrest, associated with accumulation of phospho-WEE1. Subsequent addition of the WEE1 inhibitor AZD1775 in combination significantly enhanced the induction of apoptotic cell death in TKI-sensitive and -resistant cell lines as compared to both danusertib and volasertib alone and to the simultaneous combination. This schedule indeed induced a significant increase of the DNA double-strand break marker γH2AX, forcing the cells through successive replication cycles ultimately resulting in apoptosis. Finally, combination of danusertib or volasertib+AZD1775 significantly reduced the clonogenic potential of CD34+ CML progenitors from BC patients. Our results may have implications for the development of innovative therapeutic approaches aimed to improve the outcomes of patients with multi-TKI-resistant or BC CML.
Manuela Mancini, Cecilia Monaldi, Sara De Santis, Michela Rondoni, Cristina Papayannidis, Chiara Sartor, Antonio Curti, Samantha Bruno, Michele Cavo, and Simona Soverini
MDPI AG
Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. It is well known that Aurora kinase A (AKA) over-expression promotes tumorigenesis, but its role in the pathogenesis of systemic mastocytosis (SM) has not yet been investigated. Evidence from the literature suggests that AKA may confer cancer cell chemo-resistance, inhibit p53, and enhance Polo-like kinase 1 (Plk1), CDK1, and cyclin B1 to promote cell cycle progression. In this study, we aimed to investigate the pathogenetic role of AKA and Plk1 in the advanced forms of SM. We demonstrate here, for the first time, that SM cell lines display hyper-phosphorylated AKA and Plk1. Danusertib (Aurora kinase inhibitor) and volasertib (Plk1 inhibitor) inhibited growth and induced apoptotic cell death in HMC-1.1 and -1.2 cells. Their growth-inhibitory effects were associated with cell cycle arrest and the activation of apoptosis. Cell cycle arrest was associated with increased levels of phospho-Wee1. Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA ± Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM.
Sara De Santis, Cecilia Monaldi, Manuela Mancini, Samantha Bruno, Michele Cavo, and Simona Soverini
Informa UK Limited
Abstract Protein kinases (PKs) play crucial roles in cellular proliferation and survival, hence their deregulation is a common event in the pathogenesis of solid and hematologic malignancies. Targeting PKs has been a promising strategy in cancer treatment, and there are now a variety of approved anticancer drugs targeting PKs. However, the phenomenon of resistance remains an obstacle to be addressed and overcoming resistance is a goal to be achieved. Chronic myeloid leukemia (CML) is the first as well as one of the best examples of a cancer that can be targeted by molecular therapy; hence, it can be used as a model disease for other cancers. This review aims to summarize up-to-date knowledge on the main mechanisms implicated in resistance to PK inhibitory therapies and to outline the main strategies that are being explored to overcome resistance. The importance of molecular diagnostics and disease monitoring in counteracting resistance will also be discussed.
Samantha Bruno, Lorenza Bandini, Agnese Patuelli, Valentina Robustelli, Claudia Venturi, Manuela Mancini, Dorian Forte, Sara De Santis, Cecilia Monaldi, Alessandra Grassi,et al.
Frontiers Media SA
FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring FLT3 mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the FLT3 gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel FLT3 variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, ex-vivo studies demonstrated that this novel mutation is sensitive to midostaurin.
Simona Soverini, Sara De Santis, Cecilia Monaldi, Samantha Bruno, and Manuela Mancini
MDPI AG
Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal translocation, that converts it into a leukemic stem cell (LSC). The resulting BCR-ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell-intrinsic and -extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML.
Samantha Bruno, Manuela Mancini, Sara De Santis, Cecilia Monaldi, Michele Cavo, and Simona Soverini
MDPI AG
Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.
Cecilia Monaldi, Sara De Santis, Manuela Mancini, Samantha Bruno, Michele Cavo and Simona Soverini
Over the past decade, we have witnessed significant advances in the molecular characterization of systemic mastocytosis (SM). This has provided important information for a better understanding of the pathogenesis of the disease but has also practically impacted the way we diagnose and manage it. Advances in molecular testing have run in parallel with advances in therapeutic targeting of constitutive active KIT, the major driver of the disease. Therefore, assessing the molecular landscape in each SM patient is essential for diagnosis, prognosis, treatment, and therapeutic efficacy monitoring. This is facilitated by the routine availability of novel technologies like digital PCR and NGS. This review aims to summarize the pathogenesis of the disease, discuss the value of molecular diagnostic testing and how it should be performed, and provide an overview of present and future therapeutic concepts based on fine molecular characterization of SM patients.
Margherita Martelli, Cecilia Monaldi, Sara De Santis, Samantha Bruno, Manuela Mancini, Michele Cavo, and Simona Soverini
MDPI AG
In recent years, molecular characterization and management of patients with systemic mastocytosis (SM) have greatly benefited from the application of advanced technologies. Highly sensitive and accurate assays for KIT D816V mutation detection and quantification have allowed the switch to non-invasive peripheral blood testing for patient screening; allele burden has prognostic implications and may be used to monitor therapeutic efficacy. Progress in genetic profiling of KIT, together with the use of next-generation sequencing panels for the characterization of associated gene mutations, have allowed the stratification of patients into three subgroups differing in terms of pathogenesis and prognosis: (i) patients with mast cell-restricted KIT D816V; (ii) patients with multilineage KIT D816V-involvement; (iii) patients with “multi-mutated disease”. Thanks to these findings, new prognostic scoring systems combining clinical and molecular data have been developed. Finally, non-genetic SETD2 histone methyltransferase loss of function has recently been identified in advanced SM. Assessment of SETD2 protein levels and activity might provide prognostic information and has opened new research avenues exploring alternative targeted therapeutic strategies. This review discusses how progress in recent years has rapidly complemented previous knowledge improving the molecular characterization of SM, and how this has the potential to impact on patient diagnosis and management.
Manuela Mancini, Sara De Santis, Cecilia Monaldi, Luana Bavaro, Margherita Martelli, Gabriele Gugliotta, Fausto Castagnetti, Gianantonio Rosti, Maria Alessandra Santucci, Giovanni Martinelli,et al.
Wiley
The advent of the third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) ponatinib, active against all first(imatinib) and secondgeneration (dasatinib, nilotinib, and bosutinib) TKI-resistant BCRABL1 kinase domain mutations including the T315I, has marked a breakthrough in the therapeutic landscape of chronic myeloid leukemia (CML). However, BCR-ABL1-independent TKI resistance has also been reported to occur in a significant fraction of CML patients. In a recent study, we have proven that the over-expression and hyper-activation of the Aurora kinase A (AKA)-FOXM1 axis contribute to evade death in IM-resistant BCR-ABL1+ cells. Results presented here suggest that resistance to ponatinib may equally be BCRABL1-independent, but that does not involve the AKA-FOXM1 axis. IM-resistant patients displaying over-expression and hyper-activation of AKA may thus benefit from ponatinib treatment. In order to assess whether the molecular mechanisms underlying drug resistance show similarities in BCR-ABL1+ cells selected for resistance to imatinib or ponatinib, we generated two K562 cell line subclones resistant to either imatinib or ponatinib (K562-IR and K562-PR, respectively) by progressive increase of the drug concentrations in culture media (from 0.05μM to 10μM for IM and from 0.05nM up to 50nM for ponatinib) (Figure S1). Drug resistance was confirmed by clonogenic assays. Imatinib and ponatinib lethal doses (LD50, defined as the drug concentration which reduces cell plating efficiency by 50% as compared to untreated controls) were 29.6nM and 0.06nM, respectively, for parental K562 (K562-sensitive, K562S), and 396.7nM and 2.33nM, respectively, for K562-IR and K562-PR (Figure 1A-C and F). The pro-apoptotic effects of ponatinib on K562-S cells were significantly greater as compared to those of imatinib (Figure 1G). Interestingly, K562-IR underwent apoptotic cell death in response to ponatinib and K562-PR cells equally died in response to imatinib, suggesting that different mechanisms are involved in cell death response to the two drugs (Figure 1D,E,G). Sequencing of K562-IR and K562-PR cells excluded the presence of BCR-ABL1 kinase domain mutations, confirming that both cell lines indeed exhibited BCR-ABL1-independent resistance (data not shown). In a recent study, we showed that imatinib resistance may be associated with the over-expression and hyper-activation of the AKA/FOXM1 axis and that both AKA and FOXM1 inhibitors have a significant effect on cell survival. Here, we investigated whether ponatinib resistance exhibits a similar protein expression profile. To perform our experiments, we maintained K562-IR and K562-PR cell lines in permanent imatinib and ponatinib selection (10μM and 50nM, respectively). The enzymatic activity of BCR-ABL1 was equally inhibited in K562S, K562-IR, and K562-PR cells (Figure 1H). Moreover, both imatinib and ponatinib precluded the activation of the native c-ABL1 protein (Figure 1H). These results suggested that a BCR-ABL1-independent mechanism indeed drove resistance in both cell lines. In K562-S, we confirmed the significant reduction of AKA expression and activating phosphorylation at threonine 282 in response to imatinib, resulting, in turn, in the de-phosphorylation of an AKA target, histone H3, at serine 20. In K562-IR cells, we also confirmed over-expression and hyper-phosphorylation of AKA (Figure 1H). Moreover, we observed a significant reduction in AKA expression and phosphorylation in response to ponatinib in K562-S and -IR cells. Conversely, the slight increase in AKA expression in K562-PR cells was associated with its almost complete dephosphorylation (Figure 1H). Accordingly, the phosphorylation level of histone H3 in K562-PR cells was significantly lower compared to that of K562-IR cells, suggesting the participation of alternative regulatory mechanisms of AKA function in response to the two drugs (Figure 1H). Finally, FOXM1 (an AKA downstream target) expression and phosphorylation was significantly increased in K652-IR cells, but almost absent in K562-PR (Figure 1H). We then investigated the stress sensor growth arrest/DNA damageinducible (GADD) 45 gene, which physically associates with AKA and strongly inhibits its activity. GADD45a is a target of AKA/FOXM1 axis, acting as a repressor of cell proliferation in response to TKIs. Here, we confirmed GADD45a induction in response to imatinib in the K562-S cell line, its down-regulation in K562-IR cells and its re-induction in response to ponatinib in the same cell context (Figure 1H). Conversely, K562-PR cells exhibited a significantly higher GADD45a expression level compared to K562-S and K562-PR cells, not affected by the exposure to ponatinib (Figure 1H). Beside suppression of cell growth, GADD45a is deeply involved in the maintenance of genomic stability and in the regulation of DNA repair. In conclusion, the results presented here further support a central role for AKA in BCR-ABL1-independent IM resistance but indicate that AKA is not implicated in the development of ponatinib resistance (Figure 1H). Accordingly, inhibitory drugs of AKA-FOXM1 axis, such as the pan-AK inhibitor Danusertib or the polo-like kinase 1 (PLK1) inhibitor BI2536, proposed for clinical use to circumvent IM resistance would not be helpful to address resistance to ponatinib in BCR-ABL1 + disease. GADD45a induction in response to IM and ponatinib and its expression in ponatinib-resistant cells will deserve further consideration. A recently published study demonstrated that DNA methylation abnormalities associated with BCR-ABL1 can affect the Received: 25 October 2019 Revised: 12 December 2019 Accepted: 16 December 2019
M. Mancini, S. De Santis, C. Monaldi, L. Bavaro, M. Martelli, F. Castagnetti, G. Gugliotta, G. Rosti, M. A. Santucci, G. Martinelli,et al.
Springer Science and Business Media LLC
BackgroundChronic myeloid leukemia (CML) is a myeloproliferative disease caused by the constitutive tyrosine kinase (TK) activity of the BCR-ABL1 fusion protein. Accordingly, TK inhibitors have drastically changed the disease prognosis. However, persistence of the transformed hematopoiesis even in patients who achieved a complete response to TK inhibitors and the disease relapse upon therapy discontinuation represent a major obstacle to CML cure.MethodsThiostrepton, Danusertib and Volasertib were used to investigate the effects of FOXM1, AKA and Plk1 inhibition in K562-S and K562-R cells. Apoptotic cell death was quantified by annexin V/propidium iodide staining and flow cytometry. Quantitative reverse transcription (RT)-PCR was used to assess BCR-ABL1, FOXM1, PLK1 and AURKA expression. Protein expression and activation was assessed by Western Blotting (WB). Clonogenic assay were performed to confirm K562-R resistance to Imatinib and to evaluate cells sensitivity to the different drugs.ResultsHere we proved that BCR-ABL1 TK-dependent hyper-activation of Aurora kinase A (AURKA)-Polo-like kinase 1 (PLK1)-FOXM1 axis is associated with the outcome of Imatinib (IM) resistance in an experimental model (K562 cell line) and bone marrow hematopoietic cells. Notably, such a biomolecular trait was detected in the putative leukemic stem cell (LSC) compartment characterized by a CD34+ phenotype. Constitutive phosphorylation of FOXM1 associated with BCR-ABL1 TK lets FOXM1 binding with β-catenin enables β-catenin nuclear import and recruitment to T cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription complex, hence supporting leukemic cell proliferation and survival. Lastly, the inhibition of single components of AURKA-PLK1-FOXM1 axis in response to specific drugs raises the expression of growth factor/DNA damage-inducible gene a (GADD45a), a strong inhibitor of AURKA and, as so, a critical component whose induction may mediate the eradication of leukemic clone.ConclusionsOur conclusion is that AURKA, PLK1 and FOXM1 inhibition may be considered as a promising therapeutic approach to cure CML.
Manuela Mancini, Fausto Castagnetti, Simona Soverini, Elisa Leo, Caterina De Benedittis, Gabriele Gugliotta, Gianantonio Rosti, Luana Bavaro, Sara De Santis, Cecilia Monaldi,et al.
Wiley
FOXM1 transcription factor is a central component of tumor initiation, growth, and progression due to its multiple effects on cell cycle, DNA repair, angiogenesis and invasion, chromatin, protein anabolism, and cell adhesion. Moreover, FOXM1 interacts with β‐catenin promoting its nuclear import and transcriptional activation. Here, we show that FOXM1 is involved in the advantage of chronic myeloid leukemia hematopoiesis over the normal counterpart. FOXM1 hyper‐activation associated with BCR‐ABL1 results from phosphorylation by the fusion protein kinase‐dependent activation of Polo‐like kinase 1. FOXM1 phosphorylation lets its binding with β‐catenin and β‐catenin transcriptional activation, a key event for persistence of the leukemic stem cell compartment under tyrosine kinase inhibitor therapy. Polo‐like kinase 1 inhibitor BI6727, already advanced for clinical use, breaks β‐catenin interaction with FOXM1, hence hampering FOXM1 phosphorylation, β‐catenin binding, nuclear import, and downstream signaling. In conclusion, our results support Polo‐like kinase 1/FOXM1 axis as a complementary target to eradicate leukemic early progenitor/stem cell compartment in chronic myeloid leukemia. J. Cell. Biochem. 118: 3968–3975, 2017. © 2017 Wiley Periodicals, Inc.
Chiara Leoni, David A. Stevenson, Lucilla Martini, Roberto De Sanctis, Giovanna Mascolo, Francesca Pantaleoni, Sara De Santis, Ilaria La Torraca, Silvia Persichilli, Paolo Caradonna,et al.
Elsevier BV
INTRODUCTION
Costello syndrome (CS) is a multisystemic disorder characterized by postnatal reduced growth, facial dysmorphism, cardiac defects, cognitive impairment, skin and musculo-skeletal anomalies, and predisposition to certain cancers. CS is caused by activating germline mutations in the HRAS proto-oncogene. Similar to what is observed in other RASopathies, CS causative HRAS mutations promote enhanced signal flow through the RAF-MEK-ERK and PI3K-AKT signaling cascades. While decreased bone mineralization has been documented in other RASopathies, such as neurofibromatosis type 1 and Noonan syndrome, systematic studies investigating bone mineral density (BMD) are lacking in CS.
MATERIALS AND METHODS
Dual-energy X-ray absorptiometry (DXA) was utilized to assess BMD and body composition (fat and fat-free mass) in a cohort of subjects with molecularly confirmed diagnosis of CS (n = 9) and age-matched control individuals (n = 29). Using general linear regression, subtotal body (total body less head), lumbar, femoral neck and femur BMD parameters were compared considering age, sex, body mass index (BMI) and Tanner stage. Blood and urine biomarkers of bone metabolism were also assessed.
RESULTS
All individuals with CS showed significantly lower mean values of subtotal, lumbar and femoral neck BMD compared to the control group (p ≤ 0.01). Similarly, mean total body mass and fat-free mass parameters were lower among the CS patients than in controls (p < 0.01). Low 25-OH vitamin D concentration was documented in all individuals with CS, with values below the reference range in two patients. No significant correlation between vitamin D levels and BMD parameters was observed.
DISCUSSION
CS belongs to a family of developmental disorders, the RASopathies, that share skeletal defects as a common feature. The present data provide evidence that, similar to what is recently seen in NF1 and NS, bone homeostasis is impaired in CS. The significant decrease in BMD and low levels of vitamin D documented in the present cohort, along with the risk for pathologic fractures reported in adult individuals with CS, testifies the requirement for a preventive treatment to alleviate evolutive complications resulting from dysregulated bone metabolism.
Publications
FOXM1 TRANSCRIPTION FACTOR OVER-EXPRESSION IN CHRONIC MYELOID LEUKEMIA: A NEW COMPONENT OF BCR-ABL1+ LEUKEMIC STEM CELL PERSISTENCE UNDER TYROSINE KINASE INHIBITOR THERAPY. 10.1002/
HYPER-ACTIVATION OF AURORA KINASE A-POLO-LIKE KINASE 1-FOXM1 AXIS PROMOTES CHRONIC MYELOID LEUKEMIA RESISTANCE TO TYROSINE KINASE INHIBITORS. 10.1186/s13046-019-1197-9.