David Cruz Hernandez

Acute leukaemia, like most blood cancers, arises from the accumulation of multiple genetic or epigenetic changes in normal cells. These changes are gradually acquired and progressively induce cellular differentiation arrest. Therefore, leukaemias are preceded by a preleukemic state where some but not all genetic or epigenetic changes provide a clonal advantage and delay cellular differentiation. A comprehensively understanding of this preleukemic state can offer opportunities for early diagnosis, prevention and eradication of leukaemia propagating cells. 

For instance, myeloid leukaemia of Down syndrome (ML-DS), an acute leukaemia with megakaryoblastic and erythroid features, is preceded by a temporally distinct but clonally related preleukemic state known as Transient abnormal myelopoiesis or TAM. TAM arises from the cooperation of trisomy 21 and a truncating mutation in the gene encoding the key transcription factor GATA1. Single allele mutations in genes encoding the cohesin complex are often required to transform the preleukemic clone into frank leukaemia.  Despite having a comprehensive understanding of the genetic lesion required for leukaemia transformation, a complete molecular mechanism of differentiation arrest is not yet known. 

As a DPhil student in the Vyas lab, I employ gene editing technologies, transcription factor occupancy mapping technologies, multiparameter flow cytometry, as well as state of the art single cell transcriptomics, with the goal of understanding the molecular mechanism of differentiation delay/arrest caused by oncogenic cooperation between mutant GATA1 and trisomy 21.