Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes

Abstract

IntroductionThe low-risk myelodysplastic syndromes (MDSs) refractory anemia (RA) and RA with ringed sideroblasts (RARS) are characterized by profound anemia and transfusion dependency, and a relatively low risk of progression to acute myeloid leukemia. 1,2 In RARS, the anemia is mirrored by hyperplastic but severely ineffective erythropoiesis due to increased apoptosis of erythroid progenitors. 3 The erythropoiesis of RA patients is also inadequate with apoptotic features, but may range from hypo-to hyperplastic, and shows no or few ringed sideroblasts. [4][5][6] The pathogenesis of RA anemia seems to be more heterogeneous, including T-cellmediated bone marrow failure in a subset of patients. 7,8 We have recently demonstrated that the erythroid apoptosis of low-risk MDS is initiated at a very early stage of stem cells and is associated with mitochondrial release of cytochrome c with subsequent activation of caspase-9 and effector caspase-3. Importantly, in RARS, granulocyte colony-stimulating factor (G-CSF) inhibits spontaneous release of cytochrome c, loss of mitochondrial membrane potential, and caspase activation, and restores erythroid proliferation. 9,10 Iron is predominantly stored in ferritin within cells. The multiple forms, or isoferritins, that can be found in human tissues are composed of variable proportions of 2 subunits: L-ferritin (light) and H-ferritin (heavy), encoded by genes located on chromosomes 11 and 19, respectively. Since free iron is potentially harmful to the cell, it is sequestered and detoxified to the less soluble ferric form by ferroxidase activity. H-ferritin (HF) exerts most of its ferroxidase activity in the cytosol. 11,12 Recently, a novel mitochondrial ferritin gene (MtF) was reported. This intronless gene contains a mitochondrial localization signal and is expressed in the mitochondrial matrix. It exhibits more than 75% sequence identity to the HF gene. 13,14 Mature erythroblasts from patients with X-linked sideroblastic anemia and RARS, in contrast to normal erythroblasts, express MtF 14 ; however, it is still unknown at which stage of erythroid differentiation this abnormal expression appears.The main task for the mitochondrion is to produce energy (adenosine triphosphate [ATP]). This occurs in the respiratory chain, consisting of 5 multiprotein enzyme complexes (I-V) and 2 15 Cytochrome c is closely associated with complex IV (cytochrome c oxidase) and has a major function to mediate the electron transport between complex III and IV. However, cytochrome c is also a key player in the regulation of apoptosis. 16,17 Erythroid differentiation requires activation of the erythropoietin (Epo) receptor followed by activation of the Jak-Stat pathway. This process is modulated by a complex network of transcription factors via activation of a set of target genes. GATA-1 plays a crucial role in erythroid development, and can switch the common lymphoid progenitors and granulocyte/monocyte progenitors toward megakaryocyte/erythrocyte lineage. 18,19 Epo induces globin gene expression an...

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

“…It is well recognized that there is a higher bone marrow apoptotic index in the bone marrow of low-risk MDS patients compared with high-risk MDS and MDS-AML. [38][39][40] Advanced MDS is characterized by high levels of genomic instability with a concomitant increase in cytogenetic abnormalities in comparison with early MDS. DNA damage facilitates activation of the DNA damage response (DDR) and DNA damage checkpoint pathways, which can then lead to cell cycle arrest, apoptosis, repair or cell senescence.…”

SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts

“…Although there is extensive evidence implicating abnormal expression of genes involved in heme biosynthesis, iron processing and altered mitochondrial function in the pathogenesis of RARS, none have been translated to targeted and improved therapies for these diseases. 15,16 It is possible that the role of the spliceosome in RARS and related diseases is not restricted to SF3B1, and may involve other components of the splicing machinery. This prompted us to also perform genomic sequencing of two other spliceosome components associated with SF3B1: SF3B14 and SF3B4.…”

Erythroid precursors from patients with low-risk myelodysplasia demonstrate ultrastructural features of enhanced autophagy of mitochondria

“…Moreover, the autophagic vacuoles were not only present in mature, but also in immature erythroblasts, indicating that mitochondrial autophagy in MDS is more pronounced and occurs earlier in the differentiation program. A recent study of Tehranchi et al 3 demonstrated that MDS CD34 þ cells have an enhanced expression of genes encoding for the erythroid lineage. Intrinsic defects in the programming of erythroid differentiation might be responsible for the early initiation of the autophagic process.…”

“…These events might be initiated by mitochondrial dysfunction owing to accumulation of reactive oxygen species (ROS) resulting from aberrant iron mitochondrial distribution in ringed sideroblasts. 3 Loss of mitochondrial transmembrane potential can also induce autophagy, a natural degradative process in which cytoplasmic material, including organelles and macromolecules, is segregated into double-membraned vesicles (autophagosomes), which are subsequently degraded in a lysosomal dependent manner. 4 During terminal differentiation erythroid cells undergo enucleation and removal of organelles.…”