https://orcid.org/0000-0002-1070-0727
In a landmark study reported in this issue of Blood, Sato et al have significantly deepened our understanding of Down syndrome–related myeloid neoplasms, providing an expanded view on the mutational landscape that underlies the transition from transient abnormal myelopoiesis (TAM) to myeloid leukemia of Down syndrome (ML-DS).1 Their seminal work not only uncovers novel genetic aberrations but also establishes a clear correlation between specific mutations and patient prognoses. These findings have clinical ramifications, pointing the way toward targeted therapeutic strategies.
The genesis of leukemia involves the complex interplay of genetic mutations and chromosomal alterations. Chromosome 21 is often at the center of such changes and is present in 3 copies in Down syndrome. This unique genetic backdrop makes ML-DS an informative model for understanding the impact of numerical chromosome alterations in combination with specific gene mutations.2 TAM, a precursor to ML-DS occurring in up to 30% of neonates with Down syndrome,3 is primarily driven by mutations in the GATA1 gene in fetal hematopoietic cells carrying trisomy 21. The evolution to ML-DS depends on additional mutations, most of them in members of the cohesin complex or JAK-STAT signaling pathway.2,4 Despite generally favorable outcomes in ML-DS, the prognosis in case of relapse or refractoriness is dire,5,6 a problem that Sato et al’s comprehensive genetic profiling will help address.
Their exhaustive analysis of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia samples coupled with thorough cell line studies identified several previously unknown mutational targets. Among these, the discovery of RUNX1 partial tandem duplications (PTDs) and the inactivating mutations in IRX1 and ZBTB7A are particularly notable, occurring in 13.7%, 16.2%, and 13.2% of patients with ML-DS, respectively. Specifically, the exclusive presence of RUNX1 PTDs in ML-DS samples underscores the genetic uniqueness and intricacy of DS-related leukemia. Further analysis revealed that RUNX1 PTD’s main consequence is not the generation of a significant transcript but the upregulation of RUNX1A expression through the addition of an extra promoter. RUNX1 isoform disequilibrium with RUNX1A bias has recently been shown to be key to ML-DS pathogenesis.7 Therefore, Sato et al provide a novel key mechanism of how the expression of oncogenic RUNX1A is boosted in ML-DS blasts.
A unifying theme among the mutations of RUNX1, IRX1, and ZBTB7A is the activation of MYC and E2F target genes. Although more studies using mouse models and primary cells are needed to clarify how exactly IRX1 and ZBTB7A contribute to ML-DS development and how they inhibit MYC/E2F, the study by Sato et al positions MYC at the heart of trisomy 21-associated leukemogenesis: the intricate balance of fetal liver signaling, the GATA1 mutation, and trisomy 21-associated RUNX1A bias results in a failure to regulate the MYC and E2F pathways, leading to TAM7,8 (see figure). The acquisition of additional mutations, such as those in RUNX1, IRX1, and ZBTB7A, release another brake on the MYC and E2F pathways, pushing the progression to ML-DS in the bone marrow microenvironment (see figure). Further research is needed to determine whether cell-intrinsic or cell-extrinsic factors make this extra push necessary.
Distinct role of MYC and E2F pathways in developing ML-DS. Simplified model showing the proposed role of MYC and E2F in developing ML-DS. In normal fetal hematopoiesis in the liver (A), GATA1 and RUNX1C inhibit MYC and E2F pathways. In cells with trisomy 21 and a GATA1 mutation, shortened GATA1s and RUNX1A bias fail to repress MYC and E2F, leading to TAM. After birth in the bone marrow (B), additional mutations are needed for uncontrolled MYC and E2F activation. Sato et al show that RUNX1-PTD and the disabling mutation in IRX1 and ZBTB7A can cause MYC and E2F activation, resulting in ML-DS. The figure was created with BioRender.com.
Distinct role of MYC and E2F pathways in developing ML-DS. Simplified model showing the proposed role of MYC and E2F in developing ML-DS. In normal fetal hematopoiesis in the liver (A), GATA1 and RUNX1C inhibit MYC and E2F pathways. In cells with trisomy 21 and a GATA1 mutation, shortened GATA1s and RUNX1A bias fail to repress MYC and E2F, leading to TAM. After birth in the bone marrow (B), additional mutations are needed for uncontrolled MYC and E2F activation. Sato et al show that RUNX1-PTD and the disabling mutation in IRX1 and ZBTB7A can cause MYC and E2F activation, resulting in ML-DS. The figure was created with BioRender.com.
Sato et al’s findings provide more than just a deeper understanding of ML-DS pathogenesis; they highlight the significant therapeutic potential of targeting MYC signaling. Given the challenges associated with directly targeting MYC, the authors propose leveraging bromodomain-containing protein 4 (BRD4) inhibitors or other MYC-targeting strategies as promising approaches.
Moreover, the study sheds light on the clinical implications of ML-DS’s genetic landscape, particularly the association of genetic alterations in CDKN2A, TP53, ZBTB7A, and JAK2 with poor prognoses. The findings of specific mutations’ correlation with lower survival rates underscore the importance of these genetic markers to help refine treatment strategies and risk stratification. Patients with CDKN2A deletions or TP53 mutations who have a substantially lower event-free survival may require alternative frontline therapies.
In conclusion, the comprehensive genomic analysis and functional validation by Sato et al is a major advance in our understanding of the genetic factors that influence TAM’s progression to ML-DS. The authors have put MYC at the core of ML-DS pathogenesis. By identifying new genetic targets and linking them with patient survival, this study provides the basis for future basic and clinical research to improve outcomes for patients with ML-DS. These insights are not only applicable for children with Down syndrome, but also for patients with all types of leukemia that involve numerical changes of chromosome 21.
Conflict-of-interest disclosure: J.-H.K. has advisory roles for Bluebird Bio, Boehringer Ingelheim, Novartis, Roche, and Jazz Pharmaceuticals.
