Molecular mechanisms underlying pediatric leukemia development and treatment
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Yearly about 70-90 new ALL cases are diagnosed in Sweden and the incidence peaks at 2-5 years of age. It is characterized by an expansion of immature B or T lymphocytes. The disease is heterogeneous and the subtypes are further divided into more than 10 different genetic subgroups characterized by recurring genetic abnormalities that include chromosomal translocations, gene amplifications, and mutations. These, however, are insufficient to fully explain ALL pathogenesis as they fail to induce leukemia in in vivo models indicating that additional yet uncovered factors are involved.
We support a large sample collection of live-frozen cells purified from bone marrow and peripheral blood of pediatric patients with acute leukemia (under Stockholm Medical Biobank) and use this material in accordance with the ethical permits to study mechanisms of development and resistance to therapy in ALL and AML.
Our goal is to improve our understanding of the molecular mechanisms underlying development of ALL and to identify novel biomarkers and novel targets for therapy. Using primary samples, we focus on the large-scale RNA and protein analysis of the molecular landscape of ALL. This data will allow identifying signatures of different signalling pathways in the various genomic sub-groups of ALL. Two of the pathways will be specifically in focus: STAT3 and autophagy; their activity may serve as a biomarker for the use of targeting drugs against these pathways that we are developing.
Relapsed ALL is commonly associated with a highly resistant disease and a poor prognosis. The clones at relapse may be pre-existing in the diagnostic sample. These are leukemia initiating cells, stem-like cells, distinct from proliferating leukemic blasts, first discovered in AML. They are not so well-defined but are not readily eliminated by therapy. M. Enge’s group at OncPat study this heterogeneity within the leukemic cell population by single-cell sequencing of diagnostic vs. relapsed samples from the same individual. Using specific characteristics or biomarkers, such as cell surface markers, would allow sorting out these cells from the bulk of ALL cells at diagnosis and study the activity and role of the pathways of our interest, such as STAT3 and autophagy.
One of the key drugs in the treatment of pediatric ALL, glucocorticoid (GC) dexamethasone (Dex), induces apoptotic cell death of ALL cells. We found that prior apoptosis an extensive autophagy was induced. Interestingly, Dex profoundly affect leukemic cell energy metabolism by inhibiting glucose uptake and utilization. However, data suggested that inhibition of glucose metabolism per se will not activate autophagy or cell death in these cells. By assessing the global metabolic and protein changes induced by Dex, we found several pathways to be largely affected including glutamine synthesis and lysosomal function. These metabolic features modulated by Dex in leukemic cells may be responsible for the resistance to the GC-treatment in ALL.
- Mats Heyman at The Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children’s Hospital.
- R. Nilsson, CMM, Bioclinicum, KI
- J. Lehtiö, M. Westerlund and R. Jafari, OncPat, KI and SciLife
- M. Enge and V. Zachariadis, OncPat, Bioclinicum, KI