As many of you will know hydroxycarbamide is the only drug licensed for the treatment of sickle cell disease. It’s potential benefits in sickle cell were only discovered by accident, many years ago, when patients were being treated with the drug for something else entirely and were noted to have increased amounts of foetal haemoglobin (Hb F) in their blood. In a similar fashion, researchers in the US have just reported investigations into another drug, pomalidomide, which was also found to increase Hb F, when it was being used to treat a completely different disease, in this case, multiple myeloma, a form of blood cancer.
Large amounts of Hb F, whether occurring naturally or stimulated by taking hydroxycarbamide, inhibit sickling and greatly improve patients lives. Many drugs have the potential to increase Hb F , so why is pomalidomide any different? Well, importantly it is already being used to treat patients with multiple myeloma, so we know it can be given safely to people and its effect on Hb F production appears to be very dramatic.
The researchers in the US found that in human bone marrow cells, cultured in a test tube, and in mice, genetically engineered to have sickle cell disease, pomalidomide increased Hb F production x5-6 fold, raising Hb F levels from a baseline of 5% to a maximum of 30%. In comparison, hydroxycarbamide only achieved a modest x2 increase in Hb F. In the mice with sickle cell disease, pomalidomide also reduced the production of sickle haemoglobin (Hb S) by 40%, a very significant decrease. So, pomalidomide reduces the synthesis of Hb S, the “bad guy” and replaces it with Hb F, the “good guy”.
Pomalidomide was found to work by significantly reducing, by up to 70%, the concentration of many of the chemicals, or transcription factors, which normally silence the gamma globin genes which make Hb F. These chemicals include the weirdly named SOX6, GATA1, KLF1 and LSD1 and, most importantly, the “master regulator” of gamma globin gene silencing, BCL11A. Removing these inhibitors allowed the gamma globin genes to start working again producing Hb F. In fact, pomalidomide appeared to re-programme the haemoglobin producing cells so that they behaved more like bone marrow cells from a newborn baby, when virtually all the haemoglobin produced is Hb F, rather than bone marrow cells from an adult.
These exciting results mean that pomalidomide can now be added to the growing list of drugs which increase the production of Hb F. It remains to be seen whether, when pomalidomide is used to treat patients with sickle cell disease, increased Hb F production is translated into reduced sickling and significant clinical improvement.
Pomalidomide reverses gamma-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors Brian M. Dulmovits, Abena O. Appiah-Kubi, Julien Papoin, John Hale, Mingzhu He, Yousef Al-Abed, Sebastien Didier, Michael Gould, Sehba Husain-Krautter, Sharon A. Singh, Kyle W. H. Chan, Adrianna Vlachos, Steven L. Allen,Naomi Taylor, Philippe Marambaud, Xiuli An, Patrick G. Gallagher, Narla Mohandas, Jeffrey M. Lipton, Johnson M. Liu and Lionel Blanc. Blood (2016), volume 127, pages 1481-1492
The foetal haemoglobin story just got more complicated – 12th March 2015
More on hydroxycarbamide – 7th January 2015
Homing in on BCL11A – 26th July 2014