The Hemostasis-Inflammation Connection:
The Bugs Already Know About It

As this year’s annual meet-ing winds down, we should note that a multitude of different sessions dealt with the identification of potential pathogenetic genetic mutations responsible for a wide range of hematopoietic disorders.

During Sunday’s plenary session, Dr. Calado described mutations in the TERT gene, encoding for telomerase reverse transcriptase. Dr. Calado and his colleagues showed that mutations that affect the enzyme-binding region of TERC or mutations in TERT could lead to a constitutionally reduced stem cell compartment and thus appear to be genetic risk factors for the development of what had previously appeared to be “acquired” aplastic anemia. Because of their work, we now need to put acquired in quotation marks because it may not be completely acquired; part of it may be a constitutionally small stem cell compartment that then gets hit by other stressors causing marrow failure.

This same group of investigators further expanded on this work on Monday during a simultaneous session in which they also identified mutations in the telomere-binding proteins: telomeric repeat binding factors 1 and 2 (TERF1 and TERF2), and TERF1-interacting nuclear factor 2 (TIN2). Their work suggests that novel mutations in these three genes and specific haplotypes may confer risk for aplastic anemia.

Another very stimulating simultaneous session on Monday morning was the Regulation of Gene Transcription – Lineage Selection Session. Attendees at this session heard six abstract presentations, all dealing with genes such as PU.1, Runx1, Evi1, and GATA-2 that control lineage selection. On Monday afternoon, there was a simultaneous session, entitled “Molecular Regulation of Hematopoiesis,” that covered many steps of regulational control of hematopoiesis. Dr. Grenda led off the session describing how gain-of-function mutations in the GCSF receptor confer a strong competitive advantage for these mutated cells over their normal counterparts. Dr. Sloand next described how treatment with G-CSF in some patients with aplastic anemia and congenital neutropenia can lead to preferential expansion and proliferation of pre-existing monosomy seven cells, apparently a result of increased sensitivity due to altered amounts of the truncated form of the G-CSF receptor. Another interesting abstract in this session dealt with regulation of mRNA translational control and the balance between expansion and differentiation of erythroid progenitors. More and more we are beginning to realize that RNA translational control plays a critical regulatory role in the cell. Bottom line, it’s not just DNA and protein, RNA plays a big role in the middle.

In “The Microenvironment and The Immune System” simultaneous session on Monday afternoon, Dr. Le Blanc presented an abstract that many of us might consider “off the beaten path” for an ASH meeting, but nevertheless this proved to be a stimulating and enlightening presentation. Dr. Le Blanc described her team’s efforts to perform an in utero transplantation of allogeneic fetal mesenchymal stem cells to correct severe osteogenesis imperfecta. A female fetus with multiple intrauterine fractures was transplanted at 32 weeks of gestation with HLA-mismatched male fetal mesenchymal stem cells. Will wonders never cease!

Finally, two interesting poster sessions dealt with similar issues of genetic regulation. The first was actually held way back on Saturday (boy does that seem like a long time ago). That poster session was entitled “Regulation of Gene Transcription – Erythroid/Myeloid.” If you’re not too burned out, I would highly recommend reading through these abstracts (# 1595 – 1618) while you’re waiting on your flight to go home. The other poster session was “Bone Marrow Failure – Acquired and Constitutional,” which took place yesterday. Again, great reading material in these abstracts (# 2814 – 2843).