Histiocytoses and Hematology - research projects

Hemophagocytic lymphohistiocytosis (HLH)

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.

Primary (genetic) HLH / familial HLH (FHL)

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 (PRF1) 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.

Currently we aim to improve diagnostics of FHL and to improve treatment strategies of patients with primary HLH. We are also interested in exploring if carriership of FHL genes is associated with other health problems.

Secondary (acquired) HLH

The clinical hallmark of HLH is massive inflammation (“hyperinflammation”). We are increasingly interested various forms of secondary HLH, including infection-associated HLH, malignancy-associated HLH and rheuma-associated HLH, in children as well as adults. In international collaboration, we have recently prepared recommendations for the use of etoposide-based treatment in secondary HLH, recommendations for management of HLH in adults, and recommendations for management of HLH in intensive care units (ICU).

Our current studies aim to improve survival in infection-associated HLH (including dengue-HLH), malignancy-associated HLH, rheuma-associated HLH and HLH in the ICU. We also aim to understand the underlying biology causing secondary HLH.  

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 hyperinflammation.

Contacts:

Tatiana von Bahr Greenwood, MD; Pediatrician
Elisabet Bergsten, PhD; Research coordinator, Data Manager
AnnaCarin Horne, MD, PhD; Senior researcher; Consultant
Marie Meeths, MD, PhD; Pediatrician
Alexandra Löfstedt, MD, PhD-student; Resident in pediatrics
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 with a highly variable clinical picture. Bone and skin are the most common organs affected, and other organs that may be involved include the liver, spleen, bone marrow, lungs and CNS. CNS involvement often causes endocrine affection, and sometimes a slowly progressive, potentially devastating, neurodegeneration. Together with Sahlgrenska University Hospital in Gothenburg we have developed valuable tools for assessing and monitoring neurodegenerative CNS-LCH. Our aims are to elucidate etiology and pathophysiologic mechanisms of LCH, and to reduce mortality and late effects.

The classical treatment typically involves mild chemotherapy, such as vinblastine, methotrexate, 6-mercaptopurine, corticosteroids, and vincristine, but very toxic chemotherapy such as high doses of cytarabine and 2-CdA in combination have been suggested as salvage therapy regimens.

LCH is currently viewed as an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Importantly, targeted inhibition of the MAPK pathway has improved survival further. The therapeutic effect in neurodegenerative CNS-LCH, which affects > 20% of all LCH patients and also causes most of the severe late effects, is still not well known.

One current aim is to improve survival and reduce late effects. 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. We also evaluate targeted inhibition of the MAPK pathway in LCH in general and with regard to CNS-LCH. We also study inactivation of drugs used in LCH, and how to reduce such inactivation. Another current aim is to better understand the underlying biology causing LCH.  

Contacts:

Désirée Gavhed, PhD; Research coordinator
Tatiana von Bahr Greenwood, MD; Pediatrician
Egle Kvedaraite, MD; Board certified physician
Magdalini Lourda, PhD; Assistant professor (affiliated)
Selma Olsson Åkefeldt, MD, PhD; Pediatrician
Daniel Hagey, PhD; Postdoc (affiliated)
Jan-Inge Henter, MD, PhD; Professor; Senior consultant in pediatric hematology/oncology

Acute leukemias

Acute myeloid leukemia accounts for 10-20% of childhood leukemia 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 thereby determines the sensitivity to ara-C. Moreover, we demonstrated that leukemic SAMHD1 expression has a negative impact on overall survival in children with AML treated with ara-C. Mice with SAMHD1-expressing pediatric AML xenografts were highly resistant to ara-C treatment, whereas knockout of SAMHD1 dramatically improved survival following ara-C treatment. Removing SAMHD1 from primary pediatric 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. We recently identified that non-allosteric inhibitors of the cellular protein ribonucleotide reductase (RNR) are able to block the therapy-limiting effects of SAMHD1 towards ara-CTP. Effectively, addition of low doses of RNR inhibitors re-sensitised SAMHD1-positive AML blasts to ara-C both ex vivo and in vivo. These findings prompted us to embark on a clinical trial to prospectively evaluate whether addition of RNR inhibitors to standard-AML therapy can effectively improve treatment outcome.

We have also shown that SAMHD1 is a barrier for ara-C-related drugs, so called nucleoside analogues. Those are used against a variety of paediatric and adult cancer (e.g. acute T-lymphoblastic leukaemia), and we hope that our knowledge gained on how to overcome ara-C-resistance in AML can be applied even for these diseases.

In children younger than 14 years of age, Acute Lymphoblastic Leukemia (ALL) is the most common form of leukemia, consisting of about 90% of all leukemia cases. As increasing numbers of patients with childhood leukemia are successfully cured, further efforts focused on mapping the underlying cause in order to precede disease, improve therapeutic strategies and thus improve survivor’s life quality is needed. In ALL, leukemia initiating cells hijack hematopoietic stem cell mechanisms to propagate leukemia. Why this happens is unknown. The leukemic transformation in these patients is associated with a dismal average life expectancy largely as a consequence of late effects of their treatment. Despite intense research on the topic, it is still unclear why some children develop blood cancer. Several factors have been suggested, such as chemical agents and radiation but also viral and host factors. With focus on the latter, it is unclear whether innate immune responses following exposure to viral pathogens may enhance susceptibility to, or severity of, hematological malignancies. Although the immune system being our most effective weapon against pathogen invasion, it is also a fact that immune dysregulation plays a vital role in almost all known human diseases, including cancer. Additionally, post-transcriptional RNA modification, known as ‘epitranscriptomics’, have been described by us and others as a major player of the immune system due to its role in regulating almost all aspects of RNA metabolism, such as splicing, transport, translation, stability and localization. Specifically, the most abundant RNA modification, known as m6A, have recently been described to have a biological significance for the innate immune response. Thus, RNA methylation and its connection in ALL is a major focus of our ongoing studies.

Contacts:

Nikolas Herold, MD, Dr Med, Assistant professor; Resident in pediatrics
Frida Holm, PhD; Assistant professor
Nikolaos Tsesmetzis, MSc; PhD-student
Ingrid Lilienthal, PhD; Medical student, Teaching assistant
Jan-Inge Henter, MD, PhD; Professor; Senior consultant