Sabine Strehl Group

Sabine Strehl
Email: Sabine.Strehl(at)ccri.at

Genetics of Leukemias

Leukaemia accounts for 25-35% of all childhood cancers, and is thus the most common malignancy in children. The main research of the Genetics of Leukaemia group is focused on the detection and characterization of the genetic alterations that 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 to evaluate whether they may be used as predictive markers for the refinement of risk-adapted therapy.

Team

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 characterization of new and rare genetic disease entities.
The delineation of genetic alterations with an adverse or favourable prognostic impact, hence, the identification of patients who may benefit from more intensive or alternative therapies or for whom there might be a window of opportunity for treatment de-escalation without risking a higher relapse rate or poorer overall survival.

Specific research topics

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.

Identification and characterization of rare genetic subtypes

In recent years, a multitude of novel recurrent genetic rearrangements, which define specific disease entities, have emerged in childhood leukaemia. As several of the genetic lesions are cryptic and not detectable by conventional molecular technologies, we are subjecting all so far genetically uncharacterized leukaemia samples to transcriptome (RNA) sequencing and gene expression profiling. Within the frame work of the international BFM and Ponte di Legno childhood leukaemia working groups we aim to characterize these novel and rare genetic subtypes in terms of their biological properties and their clinical relevance.

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, there is still room for improvement. 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.

Selected Articles

Fortschegger K, Husa AM, Schinnerl D, Nebral K, Strehl S. Expression of RUNX1-JAK2 in human induced pluripotent stem cell-derived hematopoietic cells activates the JAK-STAT and MYC pathways. Int J Mol Sci. 2021 Jul 15;22(14):7576.
Schinnerl D, Mejstrikova E, Schumich A, Zaliova M, Fortschegger K, Nebral K, Attarbaschi A, Fiser K, Kauer MO, Popitsch N, Haslinger S, Inthal A, Buldini B, Basso G, Bourquin JP, Gaipa G, Brüggemann M, Feuerstein T, Maurer-Granofszky M, Panzer-Grümayer R, Trka J, Mann G, Haas OA, Hrusak O, Dworzak MN, Strehl S. CD371 cell surface expression: a unique feature of DUX4-rearranged acute lymphoblastic leukemia. Haematologica. 2019 Aug;104(8):e352-e355. doi: 10.3324/haematol.2018.214353. Epub 2019 Jan 31.
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. (2017) 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
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.