Regulation of heme synthesis and heme scavengers in erythroid precursors from DBA-affected patients to restore globin/heme imbalance.⁹⁸  GATA1 expression has been found to be decreased in DBA-affected patients because of an impairment of its translation^47,78,99  or as a consequence of caspase-3 cleavage during terminal erythroid differentiation resulting from decreased levels of its chaperon, HSP70.⁸⁴  As a consequence, there is decreased expression of GATA1 transcriptional targets, including globin chains. There is also decreased expression of ALAS2, a GATA1 target, and ferrochelatase, the first and last heme biosynthesis enzymes, respectively, in the mitochondria to limit excess heme and thereby restore globin/heme balance. At the same time, there is decreased expression of TfR1 to limit iron uptake. In DBA, particularly DBA resulting from non-RPS19 mutations, there is also increased expression of heme exporter FLVCR1 (feline leukemia virus C receptor type 1), inactivation of HRI, and proteasomal degradation of BACH1 after fixation of free heme to limit excess heme in the erythroid cells. Along with limiting excess free heme, DBA erythroid cells also attempt to increase the level of globin chain translation by NRF2/Maf transcriptional activation of globin mRNA after BACH1 degradation and decreased EIF2α phosphorylation following inactivation and hypophosphorylation of HRI. The failure of these regulatory mechanisms leads to unbalanced globin/heme equilibrium, with the resultant excess of toxic heme with increased reactive oxygen species production leading to apoptosis and worsening the intrinsic defect of erythropoiesis in DBA.