Advances in molecular characterization of myeloid proliferations associated with Down syndrome

Abstract

Myeloid leukemia associated with Down syndrome (ML-DS) has a unique molecular landscape that differs from other subtypes of acute myeloid leukemia. ML-DS is often preceded by a myeloproliferative neoplastic condition called transient abnormal myelopoiesis (TAM) that disrupts megakaryocytic and erythroid differentiation. Over the last two decades, many genetic and epigenetic changes in TAM and ML-DS have been elucidated. These include overexpression of molecules and micro-RNAs located on chromosome 21, GATA1 mutations, and a range of other somatic mutations and chromosomal alterations. In this review, we summarize molecular changes reported in TAM and ML-DS and provide a comprehensive discussion of these findings. Recent advances in the development of CRISPR/Cas9-modified induced pluripotent stem cell-based disease models are also highlighted. However, despite significant progress in this area, we still do not fully understand the pathogenesis of ML-DS, and there are no targeted therapies. Initial diagnosis of ML-DS has a favorable prognosis, but refractory and relapsed disease can be difficult to treat; therapeutic options are limited in Down syndrome children by their stronger sensitivity to the toxic effects of chemotherapy. Because of the rarity of TAM and ML-DS, large-scale multi-center studies would be helpful to advance molecular characterization of these diseases at different stages of development and progression.

Prenatal diagnosis of Down syndrome combined with transient abnormal myelopoiesis in foetuses with a GATA1 gene variant: Two case reports

“…Most GATA1 mutations in TAM include either frameshift or nonsense mutations within exon 2, the GATA1 mutations create an early stop codon, resulting in a short isoform of the GATA1 protein that lacks the Nterminal activation domain, which then affect the translation of the GATA1 protein 1,9 . The detection of GATA1 mutations is important for the diagnosis of TAM.…”

“…Back in 2002, John Crispino's lab rst identi ed an important role for GATA1 mutations in Down syndrome myeloid leukaemia (ML-DS) 8 . More than 100 types of GATA1 mutations have been reported in trisomy 21 9 .…”

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review

“…These functional miRNAs form the RISC via binding to AGO. Finally, the active complex interacts with the 3′-UTR of target mRNA through complementary pairing of base pairings, causing translational repression or RNA degradation (Figure A). − Through this process, miRNAs were involved in a series of cellular processes, including apoptosis, − oxidative stress, cell proliferation, , inflammation, , hematopoiesis, , and tumorigenesis. , …”

“…A particular miRNA can target various mRNAs to induce translational repression or RNA degradation, and one mRNA can be regulated by multiple different miRNAs . By modulating gene expression at the post-translational level, miRNAs play a critical role in a series of cellular processes, including apoptosis, − oxidative stress, cell proliferation, , inflammation, , hematopoiesis, , and tumorigenesis. , Importantly, miRNAs not only have an intracellular function but also stably exist in biological fluids such as saliva, cerebrospinal fluid, plasma, serum, gingival fluid, and urine. − Therefore, circulating miRNAs are considered biomarkers of disease and can regulate gene expression in distal cells or organs. ,, …”

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development

“…Non-DS children carrying CBFA2T3::GLIS2 , KMT2A rearrangements and NUP98 :: KDM5A have a very poor prognosis ( de Rooij et al, 2016 ; de Rooij et al, 2017 ). Molecular features of ML-DS have been recently reviewed, including by our group ( Boucher et al, 2021 ; de Castro et al, 2021 ; Grimm et al, 2021 ; Li and Kalev-Zylinska, 2022 ). Here, we provide an updated summary of molecular abnormalities and emerging novel therapeutic strategies in pediatric non-DS AMKL.…”