Česká Genetická Banka

BLOOD: 15. 8. 2014

BLOOD: Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner 

"Exposure to total body irradiation (TBI) induces not only acute hematopoietic radiation syndrome but also long-term or residual bone marrow (BM) injury. This residual BM injury is mainly attributed to permanent damage to hematopoietic stem cells (HSCs), including impaired self-renewal, decreased long-term repopulating capacity, and myeloid skewing. These HSC defects were associated with significant increases in production of reactive oxygen species (ROS), expression of p16^Ink4a (p16) and Arf mRNA, and senescence-associated β-galacotosidase (SA-β-gal) activity, but not with telomere shortening or increased apoptosis, suggesting that TBI induces residual BM injury via induction of HSC premature senescence. This suggestion is supported by the finding that SA-β-gal⁺ HSC-enriched LSK cells showed more pronounced defects in clonogenic activity in vitro and long-term engraftment after transplantation than SA-β-gal^– LSK cells isolated from irradiated mice. However, genetic deletion of p16 and/or Arf had no effect on TBI-induced residual BM suppression and HSC senescence, because HSCs from irradiated p16 and/or Arf knockout (KO) mice exhibited changes similar to those seen in HSCs from wild-type mice after exposure to TBI. These findings provide important new insights into the mechanism by which TBI causes long-term BM suppression (eg, via induction of premature senescence of HSCs in a p16-Arf–independent manner). "

http://bloodjournal.hematologylibrary.org/content/123/20/3105.abstract

 

BLOOD: Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia 

"Case 1. Kierra Malcom,† a 17 year old with homozygous sickle cell disease (HbSS), was on chronic erythrocytapheresis after she suffered a stroke at 8 years of age. With the intervention, her hemoglobin S level was consistently maintained between 25% and 35%. Iron chelation was commenced at the age of 10 years. She is currently on oral deferasirox and has a ferritin level of 1400 ng/mL. T2* liver magnetic resonance imaging is normal and indicates no iron overload. Her functional score is appropriate for her age, except for poor school performance mostly attributed to frequent absences from school for sickle cell complication–related hospital admissions. Specifically, after a period of well-being for 2 to 3 years following commencement of erythrocytapheresis, she reports increasing pain symptoms over the last 5 or 6 years, chronic opioid use, and hospital admissions lasting 4 to 5 days each time, 4 to 6 times per year, interrupting her education and resulting in poor quality of life (QOL). She is keen to discuss hematopoietic stem cell transplantation (HSCT) because she has heard that it promises a cure. Her hematologist concurs with her desire to meet the transplant team to discuss HSCT. Should Kierra undergo an HSCT?

Case 2. Sonal Scher† is a 13-year-old adopted child with β thalassemia major who commenced chronic red cell transfusion therapy 8 months after birth. Iron chelation with subcutaneous desferrioxamine was started at 7 years of age following adoption. Oral chelation therapy was substituted for desferrioxamine 3 years ago, but her ferritin has remained consistently >3000 ng/mL, suggesting poor compliance. By liver magnetic resonance imaging, her hepatic iron concentration was calculated as 20 mg/g dry weight. She is of small stature and has hepatosplenomegaly. The liver is palpable 3 cm below the right costal margin and the spleen is palpable 5 cm below the left. Otherwise, she appears to be in good health. Should Sonal undergo an HSCT?

The purpose of this evidence-based review is to discuss the indications and outcomes of HSCT for sickle cell disease (SCD) and transfusion-dependent thalassemia."

http://bloodjournal.hematologylibrary.org/content/123/20/3089.full