First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia

Fazio, Grazia; Massa, Valentina; Grioni, Andrea; Bystrý, Vojtěch; Rigamonti, Silvia; Saitta, Claudia; Galbiati, Marta; Rizzari, Carmelo; Consarino, Caterina; Biondi, Andrea; Selicorni, Angelo; Cazzaniga, Giovanni

doi:10.1136/jclinpath-2019-205707

Cited by 11 publications

(12 citation statements)

References 16 publications

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“…Rare germline mutations in developmental hematopoietic genes, like ETV6, PAX5 or IKZF1, have also been shown to predispose children to ALL (30). Rare syndromes, like Cornelia de Lange and Rubinstein-Taybi syndrome that have been associated with childhood ALL, further point to a connection between variants in cohesin complex genes and CREBBP/EP300 pathway, respectively, and ALL susceptibility (33,34). Other syndromes connected to a higher risk of ALL and AML include Down syndrome (35), Noonan syndrome (36), constitutional mismatch repair deficiency syndrome (37), Fanconi anemia, and others summarized in (30,38).…”

Section: Inherited Genetic Susceptibilitymentioning

confidence: 99%

Risk Factors for Childhood Leukemia: Radiation and Beyond

Schmidt

Hornhardt

Erdmann

et al. 2021

Front. Public Health

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Childhood leukemia (CL) is undoubtedly caused by a multifactorial process with genetic as well as environmental factors playing a role. But in spite of several efforts in a variety of scientific fields, the causes of the disease and the interplay of possible risk factors are still poorly understood. To push forward the research on the causes of CL, the German Federal Office for Radiation Protection has been organizing recurring international workshops since 2008 every two to three years. In November 2019 the 6th International Workshop on the Causes of CL was held in Freising and brought together experts from diverse disciplines. The workshop was divided into two main parts focusing on genetic and environmental risk factors, respectively. Two additional special sessions addressed the influence of natural background radiation on the risk of CL and the progress in the development of mouse models used for experimental studies on acute lymphoblastic leukemia, the most common form of leukemia worldwide. The workshop presentations highlighted the role of infections as environmental risk factor for CL, specifically for acute lymphoblastic leukemia. Major support comes from two mouse models, the Pax5+/− and Sca1-ETV6-RUNX1 mouse model, one of the major achievements made in the last years. Mice of both predisposed models only develop leukemia when exposed to common infections. These results emphasize the impact of gene-environment-interactions on the development of CL and warrant further investigation of such interactions — especially because genetic predisposition is detected with increasing frequency in CL. This article summarizes the workshop presentations and discusses the results in the context of the international literature.

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Section: Inherited Genetic Susceptibilitymentioning

confidence: 99%

Risk Factors for Childhood Leukemia: Radiation and Beyond

Schmidt

Hornhardt

Erdmann

et al. 2021

Front. Public Health

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“…A considerable and solid amount of data have been generated about BRD4 in the last years, a factor that became most interesting after the development of specific inhibitors of its binding to the chromatin that were proven to be successful in preventing the growth of several cancer cellular models. Interestingly, NIPBL has been associated with cancer as well (Barber et al, 2008;Kim et al, 2013;Fazio et al, 2019;Mazzola et al, 2019) and downregulation of NIPBL arrests proliferation of breast cancer cell lines, inducing apoptosis and autophagy (Xu et al, 2015;Zhou et al, 2017), and enhances chemosensitivity of non-small-cell lung cancer cells (Xu et al, 2015;Zheng et al, 2018) and hemangioma stem cells (Liu et al, 2019). So a more detailed knowledge of the functionality of the BRD4 and NIPBL interaction may not only help to better understand the development of CdLS symptomatology but also to expand the therapeutic potential of BRD4 inhibition.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

García-Gutiérrez

García-Domínguez

2021

Front. Mol. Biosci.

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Cornelia de Lange Syndrome (CdLS) is a human developmental syndrome with complex multisystem phenotypic features. It has been traditionally considered a cohesinopathy together with other phenotypically related diseases because of their association with mutations in subunits of the cohesin complex. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably and, although their precise molecular mechanisms are not well defined yet, the potential pathomechanisms underlying these diverse developmental defects have been theoretically linked to alterations of the cohesin complex function. The cohesin complex plays a critical role in sister chromatid cohesion, but this function is not affected in CdLS. In the last decades, a non-cohesion-related function of this complex on transcriptional regulation has been well established and CdLS pathoetiology has been recently associated to gene expression deregulation. Up to 70% of CdLS cases are linked to mutations in the cohesin-loading factor NIPBL, which has been shown to play a prominent function on chromatin architecture and transcriptional regulation. Therefore, it has been suggested that CdLS can be considered a transcriptomopathy. Actually, CdLS-like phenotypes have been associated to mutations in chromatin-associated proteins, as KMT2A, AFF4, EP300, TAF6, SETD5, SMARCB1, MAU2, ZMYND11, MED13L, PHIP, ARID1B, NAA10, BRD4 or ANKRD11, most of which have no known direct association with cohesin. In the case of BRD4, a critical highly investigated transcriptional coregulator, an interaction with NIPBL has been recently revealed, providing evidence on their cooperation in transcriptional regulation of developmentally important genes. This new finding reinforces the notion of an altered gene expression program during development as the major etiological basis for CdLS. In this review, we intend to integrate the recent available evidence on the molecular mechanisms underlying the clinical manifestations of CdLS, highlighting data that favors a transcription-centered framework, which support the idea that CdLS could be conceptualized as a transcriptomopathy.

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“…Germline truncating SMC3 mutation in P6 was compatible with the clinical phenotype of CDL syndrome, a genome instability disorder called cohesinopathy (SMC3 mutations account for 1-2% of CDL). 19 Two cases of CDL-associated acute lymphoblastic leukemia (ALL) and AML have been previously reported 20,21 , but the CDL-MDS association presented here is new. CHEK2 mutations are implicated in familial breast cancer 22 and MDS.…”

Section: Resultsmentioning

confidence: 79%

“…The study cohort comprised five male patients and two female patients in whom myeloid malignancy was diagnosed at a median age of 17 (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) years after therapy for primary solid or hematologic tumors (P1-P5), arising from MDS related to Cornelia de Lange syndrome (CDL) (P6), or presenting with AML with MDS-related changes, multiple organ failure and multisystemic hyperinflammation (P7) (Table 1). The time from diagnosis of primary malignancy to development of sAML in P1-P5 ranged from 2.8 years to 15 years (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

CPX-351 induces remission in newly diagnosed pediatric secondary myeloid malignancies

Hu¹,

Caldwell²,

Onciu³

et al. 2022

Blood Advances

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Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children/adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT) but there has been no innovation in cytoreductive regimens. CPX-351, a fixed 5:1 molar ratio of liposomal cytarabine/daunorubicin, has shown favorable safety and efficacy in elderly individuals with sAML and children with relapsed de novo AML. We report the outcomes of seven young patients (six with newly diagnosed sMDS/AML and one with primary MDS/AML) uniformly treated with CPX-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-ALL; one had predisposing genomic instability disorder (Cornelia de Lange); and one MDS-related AML and multi-organ failure. The median age at diagnosis of myeloid malignancy was 17 (13-23) years. Patients received 1-3 cycles of CPX-351 (cytarabine 100mg/m2 plus daunorubicin 44mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding FLT3 inhibitor as individualized therapy in one patient. Six patients were alive and leukemia-free at 0.5-3.3 years after HCT. One patient died from disease progression before HCT. Concluding, CPX-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML warranting prospective studies.

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First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia

Cited by 11 publications

References 16 publications

Risk Factors for Childhood Leukemia: Radiation and Beyond

Risk Factors for Childhood Leukemia: Radiation and Beyond

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

CPX-351 induces remission in newly diagnosed pediatric secondary myeloid malignancies

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