bims-lifras 2023-12-03 papers

Curr Res Transl Med. 2023 Oct 18. pii: S2452-3186(23)00047-8. [Epub ahead of print]71(4): 103423

Cytogenetics in the management of bone marrow failure syndromes: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).

Wendy Cuccuini, Marie-Agnes Collonge-Rame, Nathalie Auger, Nathalie Douet-Guilbert, Lucie Coster, Marina Lafage-Pochitaloff.

Bone marrow failure syndromes are rare disorders characterized by bone marrow hypocellularity and resultant peripheral cytopenias. The most frequent form is acquired, so-called aplastic anemia or idiopathic aplastic anemia, an auto-immune disorder frequently associated with paroxysmal nocturnal hemoglobinuria, whereas inherited bone marrow failure syndromes are related to pathogenic germline variants. Among newly identified germline variants, GATA2 deficiency and SAMD9/9L syndromes have a special significance. Other germline variants impacting biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, may cause major syndromes including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Bone marrow failure syndromes are at risk of secondary progression towards myeloid neoplasms in the form of myelodysplastic neoplasms or acute myeloid leukemia. Acquired clonal cytogenetic abnormalities may be present before or at the onset of progression; some have prognostic value and/or represent somatic rescue mechanisms in inherited syndromes. On the other hand, the differential diagnosis between aplastic anemia and hypoplastic myelodysplastic neoplasm remains challenging. Here we discuss the value of cytogenetic abnormalities in bone marrow failure syndromes and propose recommendations for cytogenetic diagnosis and follow-up.

Keywords: Aplastic anemia; BMFS; Cytogenetics; DC/TBDs; Diamond-Blackfan anemia; Fanconi anemia; GATA2 deficiency; IBMFS; PNH; SAMD9/SAMD9L syndrome; Shwachman-Diamond syndrome

DOI: https://doi.org/10.1016/j.retram.2023.103423

Blood Adv. 2023 Nov 21. pii: bloodadvances.2023011165. [Epub ahead of print]

Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancy.

Kai Yu, Natalie T Deuitch, Matthew Douglas Merguerian, Lea Cunningham, Joie Davis, Erica Bresciani, Jamie L Diemer, Elizabeth J Andrews, Alice Young, Frank X Donovan, Raman Sood, Kathleen Marie Craft, Shawn N Chong, Settara C Chandrasekharappa, James Mullikin, Paul P Liu.

Familial platelet disorder with associated myeloid malignancies (FPDMM) is caused by germline RUNX1 mutations and characterized by thrombocytopenia and increased risk of hematological malignancies. We recently launched a longitudinal natural history study for patients with FPDMM. Among 27 families with research genomic data by the end of 2021, 26 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 25 of 51 (49%) patients without hematological malignancy, somatic mutations were detected in at least one of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 6 other CHIP or AML driver genes (TET2, DNMT3A, KRAS, LRP1B, IDH1, and KMT2C) were also found in two or more patients without hematological malignancy. Moreover, three unrelated patients (one with myeloid malignancy) carried somatic mutations in NFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in elderly patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring changes in somatic mutations and clinical manifestations prospectively may reveal mechanisms for malignant progression and inform clinical management. ClinicalTrials.gov identifier: NCT03854318.

DOI: https://doi.org/10.1182/bloodadvances.2023011165

Cell Death Dis. 2023 Nov 29. 14(11): 783

Arsenic trioxide extends survival of Li-Fraumeni syndrome mimicking mouse.

Jiabing Li, Shujun Xiao, Fangfang Shi, Huaxin Song, Jiaqi Wu, Derun Zheng, Xueqin Chen, Kai Tan, Min Lu.

Li-Fraumeni syndrome (LFS) is characterized by germline mutations occurring on one allele of genome guardian TP53. It is a severe cancer predisposition syndrome with a poor prognosis, partly due to the frequent development of subsequent primary tumors following DNA-damaging therapies. Here we explored, for the first time, the effectiveness of mutant p53 rescue compound in treating LFS-mimicking mice harboring a deleterious p53 mutation. Among the ten p53 hotspot mutations in IARC LFS cohorts, R282W is one of the mutations predicting the poorest survival prognosis and the earliest tumor onset. Among the six clinical-stage mutant p53 rescue compounds, arsenic trioxide (ATO) effectively restored transactivation activity to p53-R282W. We thus constructed a heterozygous Trp53 R279W (corresponding to human R282W) mouse model for the ATO treatment study. The p53R279W/+ (W/+) mice exhibited tumor onset and overall survival well mimicking the ones of human LFS. Further, 35 mg/L ATO addition in drink water significantly extended the median survival of W/+ mice (from 460 to 596 days, hazard ratio = 0.4003, P = 0.0008). In the isolated tumors from ATO-treated W/+ mice, the representative p53 targets including Cdkn1a, Mdm2, and Tigar were significantly upregulated, accompanying with a decreased level of the proliferation marker Ki67 and increased level of apoptosis marker TUNEL. Together, the non-genotoxic treatment of p53 rescue compound ATO holds promise as an alternative for LFS therapeutic.

DOI: https://doi.org/10.1038/s41419-023-06281-2