The heterogenous clinic manifestation of GATA2 deficient patients is a conundrum, the penetrance of the disease is very variable and even GATA2 carriers from the same family have a diverse symptoms or even some of them are asymptomatic. To understand this unknown aspect of the disease, I studied whether epigenetic deregulation has an impact in the GATA2 deficiency. I did the DNA methylation profiling, identifying a completely novel epigenetic signature of the GATA2 patients.
DNA sample from 17 clinically annotated GATA2-mutated individuals were referred to our laboratory from a Spanish multi-center network. The high-dimensional DNA methylation data visualization showed two major groups, GATA2-mutant carriers clustering tightly together and separately from healthy donors. Nevertheless, the asymptomatic patients P1, P16 and P17 (no apparent disease at date of sample collection at age 6, 75 and 49 years old) and member from the same family, were encompassed to healthy donor group. Notably, we observed a DNA hypermethylation pattern associated to GATA2 affected patients in bone marrow samples. This observation suggests the presence of a likely early aberrant DNA methylation at specific loci in GATA2-mutant carriers that might have a potential prognostic utility in identifying early patients at risk for disease progression. The results are included in a peer reviewed, scientific journal, focused in topics related to experimental and clinical hematology, Haematologica IF:11.04.
The second aim was to model the stepwise progression of normal cells to myelodysplastic syndrome (MDS) through the sequential introduction of first germline mutation in the GATA2 gene and after known second driver mutations such as SETBP1 (MDS) and ASXL1 (MDS/AML) by CRISPR/Cas9-mediated genome editing. Taking advantage of an in vitro blood differentiation protocol established in the host laboratory, I evaluated the impact of each mutation using the blood differentiation as a read-out. I have observed that the acquisition of three mutations in GATA2, SETBP1 and ASXL1, decreases the hematopoietic progenitors. This result is related with the clinical manifestation in GATA2 deficient patients, who presented aplasia.
Additionally, I have contributed in the writing of a review about GATA2 deficiency titled GATA2 deficiency and MDS/AML: Experimental strategies for disease modelling and future therapeutic prospects, published peer reviewed, medical journal focusing on hematology and other blood-related topics, British Journal of Haematology, IF: 8.6.
Regarding the dissemination plan, I have participated twice in the seminar of program of regenerative medicine (months 4 and 14); I have attended to the international meetings, EWOG-MDS/SAA conference (October ´21), EHA, (June ´22), the ASEICA conference with a poster presentation November´22 and I attended to the kick-off ERAPerMed meeting in Barcelona (June´22). The exploitation of this proposal was proposed in the annex1; however, due of the interruption of the fellowship, a forthcoming discussion about the intellectual property related issues with IDIBELL is planned.
