Childhood Cancer

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Unraveling GATA1s dependency in down syndrome-associated leukemia

Institution: 
Icahn School of Medicine at Mount Sinai
Researcher(s): 
Maira Bokhari
Grant Type: 
POST Program Grants
Year Awarded: 
2025
Type of Childhood Cancer: 
Acute Myeloid Leukemia (AML)
Project Description: 

Mentor Name: Elvin Wagenblast

Down syndrome (DS, or Trisomy 21, T21) is the most common cytogenetic abnormality, occurring in 1 in 700 live births, and is associated with a 150-fold higher risk of acute myeloid leukemia (AML) in early childhood. A key precursor to AML in DS is Transient Abnormal Myelopoiesis (TAM), a preleukemic condition affecting 30% of DS newborns, caused by GATA1 mutations that produce a truncated protein, GATA1s. While TAM often resolves spontaneously, 20% of cases progress to DS-associated myeloid leukemia (ML-DS) following the acquisition of tertiary mutations, predominantly in cohesin genes (e.g., STAG2). Notably, chemotherapy at the TAM stage does not prevent leukemic transformation, underscoring the need for a deeper mechanistic understanding of ML-DS progression to develop targeted interventions. Our lab identified long-term hematopoietic stem cells (LT-HSCs) as the origin of TAM, demonstrating that preleukemia arises before birth. However, it remains unclear whether GATA1s is necessary for leukemia maintenance or if ML-DS evolves to bypass its requirement. Resolving this question is critical to identifying therapeutic vulnerabilities in ML-DS. This study will use CRISPR/Cas9-mediated genome editing to revert GATA1s back to wild-type in ML-DS patient samples, which harbor T21, GATA1s, and additional mutations. Through in vitro colony formation and differentiation assays, we will determine whether correcting GATA1s restores normal hematopoiesis or if leukemia persists, suggesting GATA1s independence. We hypothesize that early-stage TAM is GATA1s-dependent, but as tertiary mutations accumulate, ML-DS becomes GATA1s-independent. If GATA1s remains essential, it may be a viable therapeutic target; if dispensable, cohesin mutations likely drive leukemic progression through alternative mechanisms. By defining how GATA1s dependency evolves in ML-DS, this study will enhance our understanding of leukemia maintenance and progression and identify new therapeutic targets for children with DS at high risk of leukemia.