Genetics of Leukaemias
Sabine Strehl, PhD
Leukaemia accounts for 25-35% of all childhood cancers, and thus, is the most common malignancy in children. The main research of the Genetics of Leukaemia group is focused on the detection and characterization of genetic alterations, which are involved in the pathogenesis and progression of the disease. The comprehensive analysis of specific genetic lesions serves on the one hand to determine their biological impact, and on the other hand to evaluate whether they may be used as predictive markers for the refinement of risk-adapted therapy.
Our research activities focus on the following sub-objectives:
- The elucidation of the role of specific genetic alterations in the pathogenesis of childhood leukaemia.
- The establishment of innovative cellular model systems to study the functional consequences of potential oncogenes.
- The identification of genes involved in genetic rearrangements and the characterization of new or rare biological disease entities.
- The delineation of genetic alterations with an adverse prognostic impact, hence, the identification of patients who may benefit from more intensive or alternative therapies.
Specific research topics
PAX5 alterations in B-cell precursor acute lymphoblastic leukaemia.
The transcription factor PAX5, which controls B-cell commitment and maintenance, is one of the most frequent targets of somatic mutation in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). These mutations comprise deletions, point mutations, internal amplifications, and gene rearrangements resulting in the expression of fusion transcripts encoding chimeric proteins. Our research focuses on elucidating the role of PAX5 lesions in the pathogenesis of childhood BCP-ALL.
Human induced pluripotent stem cells as novel cellular model system.
Due to their self-renewal and differentiation capacities human induced pluripotent stem cells (hiPSCs) hold considerable promise for in vitro disease modelling and preclinical drug testing. Therefore, we aim to in vitro differentiate normal and genetically modified (via CRISPR/Cas9 genome editing) hiPS cell lines towards specific hematopoietic lineages to determine whether this cellular model system may be used to study the oncogenicity and downstream effects of specific cancer-related genetic alterations in cell-type and differentiation stage-specific settings.
Characterization of novel and rare genetic rearrangements.
In childhood leukaemia a multitude of genetic rearrangements has been described. However, in many instances the affected genes have not been identified yet, and therefore, we aim to unravel the genes involved in rare chromosomal rearrangements, to confirm their recurrence, and to define novel genetic disease entities.
Prognostic impact of specific genetic alterations.
Although the risk stratification employed in the Austrian ALL- and AML-BFM trials has been proven as excellent guide for therapeutic decisions, a substantial proportion of patients who relapse have no known high-risk factors at the time of diagnosis. Hence, in national and international studies and in collaboration with the leading oncologists of the St. Anna Children's Hospital, we are assessing whether specific genetic lesions or combinations thereof are of predictive value and may in the future be implemented in the concept of risk-adapted therapy to further refine current stratification strategies.
Schwab C, Nebral K, Chilton L, Leschi C, Waanders E, Boer JM, Žaliová M, Sutton R, Öfverholm II, Ohki K, Yamashita Y, Groeneveld-Krentz S, Froňková E, Bakkus M, Tchinda J, Barbosa TDC, Fazio G, Mlynarski W, Pastorczak A, Cazzaniga G, Pombo-de-Oliveira MS, Trka J, Kirschner-Schwabe R, Imamura T, Barbany G, Stanulla M, Attarbaschi A, Panzer-Grümayer R, Kuiper RP, den Boer ML, Cavé H, Moorman AV, Harrison CJ, Strehl S. Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia? Blood Adv. 1: 1473-1477.
Schinnerl D, Fortschegger K, Kauer M, Marchante JR, Kofler R, Den Boer ML, Strehl S. (2015) The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia. Blood. 125:1282-1291
Fortschegger K, Anderl S, Denk D, Strehl S. (2014) Functional heterogeneity of PAX5 chimeras reveals insight for leukemia development. Mol Cancer Res. 12:595-606.
Strehl S, König M, Boztug H, Cooper BW, Suzukawa K, Zhang SJ, Chen HY, Attarbaschi A, Dworzak MN. (2013) All-trans retinoic acid and arsenic trioxide resistance of acute promyelocytic leukemia with the variant STAT5B-RARA fusion gene. Leukemia. 27:1606-1610.
Nebral K, Denk D, Attarbaschi A, Konig M, Mann G, Haas OA, Strehl S. (2009) Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia. 23:134-143.