Stephen P. Hunger, MD
This morning’s session on “Bone Marrow Failure: Stem Cells and Their Cell Cycle” at 7:30 a.m. in Hall F5 includes six abstracts that exemplify how detailed analysis of rare disorders can unravel fundamental secrets of hematopoiesis while identifying new therapeutic strategies for these disorders.
Dr. Tracie Goldberg will report on studies modeling haploinsufficiency of RPS19 and RPL5, two ribosomal proteins implicated in pathogenesis of Diamond-Blackfan anemia (DBA), in murine embryonic stem cell lines (abstract #877). Following cytokine stimulation, haploinsufficient lines displayed decreased formation of embryoid bodies and a reduction in erythroid-colony formation during differentiation to definitive hematopoietic colonies. Additionally, the Rpl5 haploinsufficient line showed severe defects in primitive erythroid-colony formation. Dr. Goldberg remarked, “these models suggest explanations for why most DBA patients are protected throughout gestation but develop red-cell failure early postnatally, while others develop hydrops fetalis.”
Proteins encoded by Fanconi anemia (FA) pathway genes play important roles in DNA repair, and recent studies have suggested that they may also be important in regulation of mitosis. Dr. Kalindi Parmar will show that FA-deficient patient cell lines and HeLa cells with knockdown of FA pathway genes had an increase in ultra-fine DNA bridges linking sister chromatids during mitosis as compared to FA-proficient cells (abstract #878). The FA protein, FANCM, was recruited to the bridges late in mitosis and FA-deficient cells displayed increased binucleated cells suggestive of cytokinesis failure. FA pathway-deficient hematopoietic cells were also hypersensitive to cytokinesis inhibitors. These findings suggest that failure of cytokinesis may play a role in bone marrow failure associated with FA.
FA cells also have a cell-cycle defect and do not slow/arrest growth following treatment with agents that induce DNA crosslinks resulting in hypersensitive clastogenic and cytotoxic response to diepoxybutane and psoralen plus ultraviolet A light (PUVA). Dr. W. Clark Lambert studied whether DNA synthesis inhibitors such as hydroxyurea (HU) and 5-fluorouracil (5-FU) might overcome the cytoclastic and cytotoxic effects of PUVA in FA cells (abstract #879). Uncorrected FA cell lines showed reduced clastogenicity and increases in viability following PUVA and treatment with HU or 5-FU, while normal cells and corrected FA cells did not show a comparable response. The authors suggest that treatment of FA patients with HU or 5-FU might prevent or delay onset of hematopoietic disorders.
Biallelic mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS) cause Shwachman-Diamond syndrome. The SBDS protein is involved in ribosome biogenesis and microtubule stabilization during mitosis. Katie Lombardo will report that SBDS promotes mitotic spindle stability by directly modifying microtubule dynamics and through a microtubule cross-linking activity (abstract #880). These functions are critical for the growth and differentiation of hematopoietic progenitors, and their data suggest that loss of SBDS promotes genomic instability leading to marrow failure and a predisposition to leukemia. These findings increase understanding of pathogenesis of Schwachman-Diamond syndrome and suggest novel approaches to treatment of this disorder.
Children with Down syndrome (DS) have unique hematologic disorders and an increased risk for leukemia. Despite increasing knowledge concerning somatic genetics of leukemia in DS, how trisomy 21 predisposes to leukemia is unknown. Natsumi Nishihama will discuss exciting results using human-induced pluripotent stem cells (hiPSCs) derived by reprogramming skin fibroblasts (via expression of OCT3/4, KLF4, and SOX2 +/- c-MYC) of patients with DS and normal controls (abstract #881). They found that hiPSCs derived from DS patients could differentiate into multiple hematopoietic cell lineages and that differentiation into the hematopoietic lineage was promoted in DS patients as compared to controls.
Telomerase complex mutations are implicated in the pathogenesis of bone marrow failure. The shelterin protein complex, including TPP1 encoded by Acd, binds and protects telomeres. Lastly, Morgan Jones will share how he used adrenocortical dysplasia (acd), a spontaneous autosomal recessive mouse mutation causing profoundly hypomorphic Acd expression, to dissect how TPP1 plays a critical role in the ability of shelterin to maintain hematopoetic stem cells (HSCs), independent of telomerase function (abstract #8825).
This session exemplifies how detailed analyses of rare blood disorders can shed light on the basic mechanisms that control hematopoiesis, which has widespread implications for treatment of these diseases, treatment of leukemias, and technological improvements in stem cell transplantation.
Dr. Hunger indicated no relevant conflicts of interest.