A Maltese family and the KLF1 discovery

In 2010, while I was working on my PhD, a Maltese family helped us understand something fundamental about blood: why some people continue to produce appreciable amounts of fetal haemoglobin long after birth. I was 28 at the time, working with colleagues at the University of Malta and Erasmus MC in Rotterdam. That family remains central to the questions I ask today.

Fetal haemoglobin, or HbF, carries oxygen before birth. Its production normally falls as adult haemoglobin takes over. Understanding why that change is incomplete in some people matters to those working on beta-thalassaemia and sickle cell disease, where retaining HbF can be beneficial.

What the family taught us

Our study identified a change in KLF1 called p.K288X. KLF1 is a transcription factor with a central role in red blood cell development. The variant introduces an early stop in the protein, removing its DNA-binding domain. In the family we studied, the people with hereditary persistence of fetal haemoglobin carried one copy of this altered gene.

The next question was how reduced KLF1 function could leave fetal haemoglobin switched on. Our experiments pointed to BCL11A, a repressor of fetal globin genes. KLF1 helps activate BCL11A as well as adult beta-globin. With less functional KLF1, BCL11A expression was reduced, providing a route through which fetal globin could remain active.

We published the work in Nature Genetics in 2010. Petros Papadopoulos, Marianthi Georgitsi and I contributed equally. The study brought together colleagues in Malta, the Netherlands, Greece and Cyprus, including Alex E. Felice, George P. Patrinos, Sjaak Philipsen and the wider author team. The family's participation made the human genetic work possible.

A simplified view of the pathway: KLF1 supports adult beta-globin production and activates BCL11A, which represses fetal gamma-globin. Based on our study and the complementary work of Zhou and colleagues. The full switching mechanism involves many more interactions.

How the field moved forward

Our finding was part of a much larger effort. Sankaran and colleagues had established BCL11A's role in 2008. The study by Zhou and colleagues, published alongside ours, showed that lowering KLF1 in adult erythroid progenitors reduced BCL11A and increased the gamma-to-beta globin expression ratio. The genetic and experimental findings helped explain the same biological relationship.

In 2013, Bauer and colleagues identified an erythroid enhancer of BCL11A, opening a way to target its regulation in red blood cells. Clinical studies reported in 2024 by Frangoul and colleagues and Locatelli and colleagues tested exagamglogene autotemcel, which edits this enhancer, in severe sickle cell disease and transfusion-dependent beta-thalassaemia. These advances reflect years of work by many research and clinical teams.

My own work has also taken other directions: documenting haemoglobinopathy variation through microattribution, and examining globin-related expression in spaceflight datasets. The settings are different, but I keep returning to how red blood cells respond when their usual regulation changes.

Why I keep returning to the family

Finding the KLF1 variant answered an important question, but it did not explain every difference between family members. Why can people who carry the same variant have quite different HbF levels? What else influences the response, and how much depends on the stage of red blood cell development?

These are questions we are still working on. We can now examine RNA expression and chromatin accessibility together, and compare the family observations with experiments from other laboratories. Each comparison helps us decide which explanations deserve closer attention. A pattern that looks convincing still has to stand up to a direct test.

I have brought this work together in the Globin Switch Atlas, so that colleagues and students can explore the observations, follow the published evidence and see where questions remain open. It is a resource I want us to keep improving as the science develops.

The Maltese family gave us a way into this biology. There is still much to learn from it.

You can find the papers in our publication index, explore the Atlas, or get in touch to discuss the work.