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Histiocytoses and Hematology - research projects

Hemophagocytic Lymphohistiocytosis (HLH) Clinical Studies

The mononuclear-phagocyte system comprises two major cell types, the macrophages and the dendritic cells, which are mainly antigen-presenting cells. Accordingly, histiocytoses are classified as either diseases with macrophage accumulation, including (familial) hemophagocytic lymphohistiocytosis (FHL or HLH), or disorders with the antigen-presenting Langerhans cell as the central cell, with Langerhans cell histiocytosis (LCH), previously called Histiocytosis X, as the most frequent disease.

We have a deep and long-lasting interest in this field. FHL is a rapidly fatal disease that most typically affects infants and young children, with a median survival of 1-2 months without treatment. We have developed the international diagnostic guidelines for HLH (1991 and 2004) and, in collaboration with clinical scientists worldwide, we coordinated the international treatment protocols (HLH-94 and HLH-2004) with the major aim to improve the therapeutic results.

In 1996 we suggested that FHL might be caused by an apoptosis defect and in 1999 we were able to show that FHL is caused by a deficiency in apoptosis triggering. Subsequently, in collaboration with other research groups in 1999, mutations in the perforin gene were revealed in a subset of FHL patients.

Additional genetic studies revealed another gene causing FHL (STX11), and a deep intronic mutation and an inversion of the gene UNC13D. Interestingly, it appears as if mutations in FHL-causing genes may be associated with an increased risk of developing malignancies, and we have shown that this is the case also for healthy carrier of FHL-causing genes, possibly due to a moderately deficient surveillance of tumor transformed cells.

The clinical hallmark of HLH is massive inflammation (“hyperinflammation”). We are increasingly interested in improving outcome for patients affected also by various forms of secondary HLH, including infection-associated HLH, malignancy-associated HLH and rheuma-associated HLH, in children as well as adults.

New diagnostic and clinical studies on HLH are in progress. We want to take advantage of our solid knowledge on HLH and hyperinflammation, and expand that knowledge to other relevant patient groups. Our ultimate goal is to improve the outcome, in all respects, of patients affected by HLH, i.e. hyperinflammation.


Tatiana von Bahr Greenwood, MD; Pediatrician
Elisabet Bergsten, PhD Research coordinator, Data Manager
AnnaCarin Horne, MD, PhD, Senior researcher; Consultant in pediatric rheumatology
Jan-Inge Henter, MD, PhD, Professor; Senior consultant in pediatric hematology/oncology

Langerhans Cell Histiocytosis (LCH)

Langerhans cell histiocytosis (LCH) is a potentially fatal disease of unknown cause. If only one organ is involved the survival is excellent whereas the 5-year survival in multisystem LCH with risk organ involvement is around 85%. In addition, there is a risk of developing permanent complications to LCH. Our aims are to elucidate etiology and pathophysiologic mechanisms of LCH, and to reduce mortality and late effects in LCH.

In very long-term follow-up studies, up to 39 years, we have shown that permanent CNS sequelae are common in LCH. With the goal to improve survival and reduction of sequelae, we try to improve monitoring of the course of the disease and evaluate clinical, laboratory and imaging tools for monitoring of disease activity. We are eager to add novel therapeutic approaches to the treatment of this disease. We participate actively in the international multicenter study LCH-IV on treatment and natural history of pediatric LCH patients, in which we coordinate the part on CNS-LCH (Stratum V).


Désirée Gavhed, PhD, Research coordinator
Tatiana von Bahr Greenwood, MD; Pediatrician
Egle Kvedaraite, MD; Intern
Magdalini Lourda, PhD, Assistant professor
Jan-Inge Henter, MD, PhD, Professor; Senior consultant in pediatric hematology/oncology

Acute leukemias

Acute myeloid leukaemia accounts for 10-20% of childhood leukaemia and 3-6% of all childhood malignancies. Despite a substantial increase in the 5-year overall survival in the NOPHO countries from below 40% (NOPHO AML-1984) to almost 70% (NOPHO AML-2004), AML still has the worst prognosis of all major diagnostic groups of childhood cancer. As of today, the most advanced treatment protocol in clinical practice (NOPHO-DBH AML-2012) has incorporated ara-C in all standard and experimental arms which is indispensable for both remission induction and consolidation.

Importantly, we have shown that the protein SAMHD1 negatively regulates the amount of intracellular ara-CTP and ara-GTP, and thereby determines the sensitivity to ara-C. Moreover, we demonstrated that SAMHD1 expression has a negative impact on overall survival in children with AML treated with ara-C. Mice with SAMHD1-expressing paediatric AML xenografts were highly resistant to ara-C treatment, whereas knockout of SAMHD1 dramatically improved survival following ara-C treatment. Removing SAMHD1 from primary paediatric patient-derived AML cells drastically increased their sensitivity towards ara-C. We now search for possible ways to use this information with the ultimate goal to improve survival in children and adults with AML.


Nikolas Herold, MD, Dr. med, postdok; ST-läkare i pediatrik
Nikolaos Tsesmetzis, MSc
Frida Holm, Assistant Professor
Jan-Inge Henter, MD, PhD, Professor; Senior consultant in pediatric hematology/oncology