The Diamond Blackfan Anemia Foundation (DBAF) extends our sincerest congratulations and warmest welcome to Diamond Blackfan Anemia Canada (DBAC). The DBAC has officially received their registered charity status and has joined the worldwide effort to support DBA patients and research.  We look forward to working closely with our Canadian friends.

Steven R. Ellis, PhD Research Director

So what's the deal with red cells and ribosomes?  Red cells don't even contain ribosomes!  So why is it that that the defect in ribosome production seen in DBA patients preferentially affects red cells?  Well, of course, the answer resides in that it is not red cells per se that are affected in DBA, but instead the red cell progenitors in the bone marrow that give rise to red cells.  And yes, these progenitors have ribosomes.  In fact, they are thought to have lots of ribosomes.  These red cell progenitors proliferate rapidly, and cells that proliferate rapidly need lots of ribosomes.  This is because for a cell to divide it must also grow, and for cells to grow, they need more ribosomes than a cell that is not growing.  The increase in ribosomes is needed to synthesize the proteins that copy DNA, make cellular membranes, provide energy, and darn near everything else it takes for cells to make new cells.  But, aren't there a fair number of other cell types in the human body that grow and divide rapidly, and if so, why aren't they affected in DBA?  These are questions that have been puzzling the DBA research community since the discovery of RPS19 as the first DBA gene back in 1999 (Draptchinskaia et al, 1999). 

Which brings us to this month's "Journal Club" paper.  In a recent issue of Blood, Ebert and colleagues make inroads into explaining the selective effect of ribosomal protein mutations on red cell production (Dutt et al).  Their studies were built upon a number of recent observations indicating that the tumor suppressor p53 plays an important role in promoting the death of cells lacking sufficient amounts of ribosomal proteins.  In their study, the Ebert group took human CD34⁺ hematopoietic progenitor cells (that were either normal or expressed reduced amounts of Rps19) and induced these cells to differentiate along the erythroid or other myeloid lineages.  Intriguingly, they found that p53 was selectively activated in cells differentiating along the erythroid lineage.  These observations would therefore seem to recapitulate some of the tissue specific hallmarks which define DBA.  Moreover, the authors show that the impaired erythroid differentiation induced by ribosomal protein haploinsufficiency can be rescued by an inhibitor of p53 function.  While this latter observation has certain therapeutic implications for DBA, it should be pointed out that the use of drugs that target what is generally thought of as the major tumor suppressor in human cells would likely entail unacceptable cancer risks.  Although there are certain caveats to the Ebert study and many important questions remain regarding the preferential sensitivity of the developing erythron to mutations in ribosomal protein genes, this manuscript nevertheless represents a very exciting development in the field. 

Recently, a colleague of mine sent me a manuscript that he felt may shed additional insight into the results reported by the Ebert group.  This colleague has insisted time and time again that heme toxicity may ultimately be responsible for the clinical features of DBA.  The manuscript he brought to my attention shows that proptoporphyrin IX binds to and activates p53 (Zawacka-Pankau et al, 2007).  Now you may recall that last "Journal Club" I mentioned that there are investigators who feel that a defect in ribosome synthesis would likely reduce levels of globin chains and cause heme to build up in red cell progenitors.  Well, protoporphyrin IX is heme without the iron, so if heme like protoporphyrin IX were to bind and activate p53, well, then you may have the smoking gun that provides the erythroid specificity of DBA.  This, as in all of my musings, involves a lot of "ifs".   Nevertheless, experiments such as those described by Ebert and colleagues transform "ifs" like these into a deeper understanding of the complex physiological aspects of DBA - which we all hope will create new avenues for treatment.  

 

 Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I, Ball S, Tchernia G, Klar J, Matsson H, Tentler D, Mohandas N, Carlsson B, Dahl N (1999) The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet 21(2): 169-175

 

Dutt S, Narla A, Lin K, Mullally A, Abayasekara N, Megerdichian C, Wilson FH, Currie T, Khanna-Gupta A, Berliner N, Kutok JL, Ebert BL Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood 117(9): 2567-2576

 

Zawacka-Pankau J, Issaeva N, Hossain S, Pramanik A, Selivanova G, Podhajska AJ (2007) Protoporphyrin IX interacts with wild-type p53 protein in vitro and induces cell death of human colon cancer cells in a p53-dependent and -independent manner. J Biol Chem 282(4): 2466-2472