The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

Abstract

Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and in signalling mediators of the JAK/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS.

Exploring the Leukemogenic Potential of GATA-1S, the Shorter Isoform of GATA-1: Novel Insights into Mechanisms Hampering Respiratory Chain Complex II Activity and Limiting Oxidative Phosphorylation Efficiency

“…A balanced expression of its two isoforms, the full-length GATA-1 FL (NM_002049.3) and the shorter variant GATA-1 S (XM_024452363.1), is required in normal hematopoiesis whereas their dysregulation in favor of the short isoform alters the differentiation/proliferation potential of hematopoietic precursors and contributes to multi-step leukemogenesis [31][32][33][34][35][36][37]. However, despite much effort, there are several unanswered questions regarding the mechanistic principles linking GATA-1 dysregulation and hematological malignancies [36,38,39]. Starting from a recent study by our group showing that GATA-1 isoforms differently influences cell redox states, generation of mitochondrial O 2 − , expression levels of SDH subunits, and sensibility to apoptosis [6], we are now able to unveil a molecular mechanism through which unbalanced expression of GATA-1 isoforms could exert a leukemogenic role by impairing complex II activity and limiting OXPHOS efficiency.…”

Advances in molecular characterization of myeloid proliferations associated with Down syndrome

“…JAK1-3 variants are identified in both ML-DS and TAM samples, however, gain-of-function mutations are only detected in ML-DS, highlighting that aberrant activation of JAK-STAT signaling is important for transition to leukemia ( Labuhn et al, 2019 ). The JAK family of tyrosine kinases (JAK1-3 and tyrosine kinase 2, TYK2) are pivotal mediators of growth factor and cytokine signaling, including downstream of thrombopoietin (TPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) ( De Castro et al, 2021 ; Moser et al, 2021 ). JAK1, JAK2 and TYK2, are ubiquitously expressed, whilst JAK3 is predominantly expressed in lymphoid and myeloid cells.…”

“…Trisomy 21 is associated with defects in hematopoiesis and the immune system. Trisomy 21 fetuses have dysregulated development of megakaryocytic, erythroid and B-cell lineages ( Laurent et al, 2020 ; De Castro et al, 2021 ). The mechanism through which an extra copy of chromosome 21 perturbs hematopoiesis and then how it cooperates with subsequent mutations to lead to TAM and ML-DS are still uncertain.…”

“…JAK3 mutations are more common than of other members of JAK family in ML-DS ( Labuhn et al, 2019 ). Under physiological conditions, JAK-STAT signaling is tightly controlled and involved in a wide range of fundamental biological processes, including cell proliferation, differentiation, apoptosis, inflammation, and blood production ( Park et al, 2016 ; De Castro et al, 2021 ; Moser et al, 2021 ). Normal megakaryopoiesis requires TPO-mediated STAT5 activation.…”

“…ML-DS pathogenesis is understood to follow a multistep clonal evolution process ( Figure 1 ). Trisomy 21 represents a “primary hit”, which alters hematopoiesis during embryonic development; acquisition of somatic GATA1s mutations represents a “secondary hit”, which promotes hematopoietic deregulation and emergence of TAM in DS newborns; additional mutations predominantly affecting chromatin and epigenetic regulators (e.g., the cohesin complex) and signaling mediators (e.g., Janus kinase 2, JAK2) represent a “tertiary hit”, which leads to ML-DS ( Labuhn et al, 2019 ; Garnett et al, 2020 ; De Castro et al, 2021 ) ( Figure 1 ). The detailed mechanism of how these events contribute to different stages of disease is still unclear.…”