By using sensitive deep-sequencing technology, we demonstrated that TP53 mutated populations may occur at an early disease stage in almost a fifth of low-risk MDS patients with del(5q). Importantly, mutations were present years before disease progression and were associated with an increased risk of leukemic evolution. TP53 mutations could not be predicted by common clinical features but were associated with p53 overexpression. Our findings indicate a previously unrecognized heterogeneity of the disease which may significantly affect clinical decision making.

In these patients with the del(5q) myelodysplastic syndrome, we identified rare and phenotypically distinct del(5q) myelodysplastic syndrome stem cells that were also selectively resistant to therapeutic targeting at the time of complete clinical and cytogenetic remission. (Funded by the EuroCancerStemCell Consortium and others.)

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...

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Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia. Within MDS, 5q− syndrome constitutes a distinct clinical entity characterized by an isolated deletion of the long arm of chromosome 5 (5q−), a relatively good prognosis, and infrequent transformation to acute leukemia. The cell of origin in 5q− syndrome as well as in other 5q-deleted MDS patients has not been established, but evidence for involvement of multiple myeloid (but not lymphoid) lineages has suggested that a myeloid-restricted progenitor rather than a pluripotent (lympho-myeloid) stem cell might be the primary target in most patients. Although in 9 patients no evidence of peripheral blood T-cell and only 1 case of B-cell involvement was found, the data herein support that 5q deletions occur in hematopoietic stem cells (HSCs) with a combined lympho-myeloid potential. First, in all investigated patients a minimum of 94% of cells in the minor CD34+CD38− HSC compartment were 5q deleted as determined by fluorescence in situ hybridization. Second, in 3 of 5 patients 5q aberrations were detected in a large fraction (25% to 90%) of purified CD34+CD19+ pro-B cells. Furthermore, extensive functional characterization with regard to responsiveness to early-acting cytokines, long-term culture-initiating cells, and nonobese diabetic/severe combined immunodeficiency repopulating cells supported that MDS HSCs in 5q-deleted patients are CD34+CD38−, but inefficient at reconstituting hematopoiesis.