#Facultyseminars: GATA2 deficiency Syndrome: modeling progression to MDS

Patients with GATA2 deficiency are at high risk of developing myelodysplastic syndrome (MDS), which may progress to acute myeloid leukemia (AML). Although germline GATA2 mutations establish a predisposing background, they are typically insufficient on their own to drive malignant transformation. Disease progression is frequently associated with the acquisition of cytogenetic abnormalities and additional somatic mutations. In pediatric GATA2-related MDS, recurrent mutations in SETBP1 and ASXL1 are commonly observed. To dissect the molecular mechanisms underlying disease onset and progression, we employ CRISPR-based stem cell modeling. Engineered GATA2-mutant CD34⁺ hematopoietic progenitors display impaired proliferation, genomic instability, and features of premature cellular aging, resulting in reduced in vivo fitness.Furthermore, we have generated the first induced pluripotent stem cell (iPSC)-based models that recapitulate the stepwise mutational trajectories observed in GATA2-related MDS patients. These models enable us to define the functional impact of secondary somatic mutations on myeloid differentiation and pre-leukemic hematopoietic stem cell priming. Collectively, our findings provide mechanistic insight into the pathways dysregulated in GATA2 deficiency and illuminate early events driving leukemic evolution.

Hosted by M. Carolina Florian – Stem cell aging

She obtained her Bachelor’s degree in Biology in 1998 from the University of Pisa and her PhD in Molecular Medicine in 2004 from the University of Milan. She pursued her postdoctoral training in Dr. Shahin Rafii’s laboratory at Weill Cornell Medical College in New York and later at the Center of Regenerative Medicine of Barcelona (CMRB), Spain. During this period, she made significant contributions to the field of cellular reprogramming, generating the first induced pluripotent stem cells (iPSCs) from cord blood stem cells (CBSCs) using only two of the four Yamanaka factors. Her work established the concept that CBSCs are intrinsically more amenable to reprogramming. Since 2020, she has led the Hematopoietic Stem Cell Biology and Leukemogenesis Group at IDIBELL and serves as Associate Professor at the University of Barcelona. Her research focuses on the molecular mechanisms regulating hematopoietic stem cell commitment, maintenance, differentiation, and malignant transformation. More recently, her research line focused on the role of predisposing genes in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Her current work integrates advanced OMIC approaches, including single-cell genomic and transcriptomic analyses, with functional studies of MDS/leukemia predisposition genes using human iPSC models, 3D co-culture systems, and xenograft mouse models.