Down syndrome is associated with abnormalities in haematopoiesis and the immune system. Children with Down syndrome (DS) have a significantly increased risk of developing certain types of leukaemia, in particular acute lymphoblastic leukaemia (DS-ALL) and acute myeloid leukaemia (AML), especially of the megakaryocytic subtype (AMKL) compared to non-Down syndrome children.
The mechanisms underlying haematopoiesis dysregulation and the development of leukaemia in DS remains uncertain. However, deregulation of genes on chromosome 21 is thought to play a major role as several genes on chromosome 21 encoding proteins such as transcription factors, signaling effectors, epigenetic regulators and miRNAs, are critical for myeloid proliferation.
In myeloid leukaemia of Down syndrome (ML-DS), mutations in key haematopoietic genetic factors, such as the transcription factor GATA1, lead to leukaemogenesis early in foetal life and consequently to a transient pre-leukaemic state called transient abnormal myelopoiesis (TAM). In most cases, the pre-leukaemia regresses spontaneously, however some children will later develop AMKL and in general have a very poor prognosis. Other mutations in genes encoding cohesion and epigenetic regulators can also result in subsequent progression to myeloid leukaemia. In the case of DS-ALL, alterations in the JAK-STAT and RAS signalling pathways are frequently observed and JAK and KRAS inhibitors may improve outcome for this type of leukaemia.
Studies conducted by researchers over the years have improved our understanding of the mechanisms responsible leukemogenesis in children with Down syndrome, providing essential information for the management of pre-leukaemia and leukaemia. However, although major improvements have been made in the treatment of leukaemia, the therapies have significant side effects and are often not curative and a significant number of children still suffer from treatment-related complications and disease relapse.
Several laboratories around the world are focusing their research on understanding Down syndrome related leukaemia in order to find new therapeutic possibilities. The aim is to find the right balance between effective curative therapies and reduced treatment-related toxicities. However, the limited availability of patient samples and the lack of appropriate models complicate this task.
This symposium brought together leading scientists and physicians from around the world who study leukaemia or treat patients with Down syndrome who have developed leukaemia to share new findings and identify potential new strategies for the management of children with DS and pre-leukaemia and leukaemia.
High quality discussions helped to define the key research and clinical questions to understand the biology of the leukaemias and share the most up-to-date treatment regimens, as well as the assessment of treatment responses and complications encountered by treated patients. In some forms of leukaemia, relapse is a major problem, and the mechanisms of relapse in children with Down syndrome were also a focus of these discussions.
The meeting was a great success, and the objectives were achieved. An article summarising the discussions and conclusions is being prepared and will be published in an international journal. The Fondation Jérôme Lejeune is proud to have initiated and contributed to the organisation of this first exceptional meeting on the subject, which will be organised every two years.
Sergi Cuartero, Ph.D: Dr. Cuartero is a Junior Group Leader at the Josep Carreras Leukemia Research Institute (Barcelona, Spain). His lab studies the role of enhancer-promoter interactions and 3D genome organization in the regulation of haematopoietic differentiation and immune function. In the past, he has shown that the cohesin complex is required for inducible gene expression in myeloid cells and that cohesin mutations in AML impair the inflammatory response. Currently, with the support of the Jerome Lejeune Foundation, the lab is trying to elucidate the role of cohesin and CTCF mutations in myeloid leukemia of Down syndrome.
Sébastien Malinge, Ph.D: Group leader of `Translational Genomics in Leukaemia` at Telethon Kids Institute (Perth, Australia), Dr Malinge`s group aims to understand the role of chromosome 21 gene dosage imbalance in leukemogenesis. He identified the kinase DYRK1A as a key player in in both myeloid and lymphoid leukemia associated with Down syndrome. Recently, his team developed the first cohort of Patient-derived xenograft of DS-ALL, comprehensively characterized at the genetic, transcriptomic and phenotypic levels. These preclinical tools have been subsequently used to test new therapeutical approaches with the view of improving outcomes for children with Down syndrome that developed leukaemia.
Sandra Ryeom, Ph.D: Dr. Ryeom is an Associate Professor of Cancer Biology at the Columbia Medical Center in New York. Her lab has a long-standing interest in understanding the role of the calcineurin-NFAT signaling pathway in regulating tumor growth and leukemogenesis in patients with Down syndrome. Notably, 4 chromosome 21 genes encode negative regulators of calcineurin-NFAT signaling and her lab has shown that these genes suppress tumor angiogenesis and promote acute megakaryoblastic leukemia in patients with Down syndrome.
André Baruchel, Hôpital universitaire Robert Debré (APHP and Université Paris Cité), Paris, France
Jean-Pierre Bourquin, University Children’s Hospital, Zurich, Switzerland
John Crispino, St. Jude Children’s Research Hospital, Memphis, United States
Sergi Cuartero, Josep Carreras Leukemia Research Institute, Barcelona, Spain
Henrik Hasle, Aarhus University Hospital, Aarhus, Denmark
Johann Hitzler, The Hospital for Sick Children. Toronto, Canada
Shai Izraeli, Schneider Children’s Medical Center of Israel, Tiqva, Israel
Jan-Henning Klusmann, Universitätsklinikum Frankfurt, KGU, Frankfurt, Germany
Andy Lane, Dana-Faber Cancer Institute, Boston, United States
Sébastien Malinge, Telethon Kids Institute, Perth, Australia
Karen Rabin, Baylor College of Medicine. Texas Children’s Cancer Center, Texas, United States
Irene Roberts, University of Oxford, Oxford, United Kingdom
Sandra Ryeom, Columbia Medical Center, New York, United States
Sarah Tasian, University of Pennsylvania Perelman School of Medicine. Children’s Hospital of Philadelphia, Philadelphia, United States
Elvin Wagenblast, Icahn School of Medicine at Mount Sinai, New York, United States