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Born 1964 in Solothurn, Switzerland. Email: j.schwaller@unibas.ch |
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Research focus Leukemia like all cancers is a genetic disease. Clinical and experimental evidence supports the hypothesis that acute leukemia is the product of several cooperating genetic alterations often presenting as fusion genes resulting from chromosomal translocations. Two functional classes can be distinguished: "class I" includes mutations mostly activating protein tyrosine kinases (and downstream/related signaling mediators) that lead to enhanced proliferation and/or survival. These mutations are sufficient to induce a leukemic phenotype in animal models. In contrast "class II" mutations mostly target transcriptional regulators (transcription factors and co-regulators) that are essential for normal hematopoietic differentiation. Structure functional analysis allowed the successful development of small molecules interfering with several "class I" mutations such as ABL, PDGFR or FLT3. We have recently identified PIM serine/threonine kinases as potential therapeutic targets for hematological malignancies. We have functionally characterized small molecule PIM kinase inhibitors with anti-leukemic activity. In addition, we found that PIM1 also mediates the interaction of hematopoietic (stem) cells with the microenvironment through regulation of the CXCR4 chemokine receptor. The molecular mechanisms of "class II" mutation-mediated leukemia is less understood. We have recently cloned and functionally characterized a new leukemogenic fusion involving the genes for nucleoporin 98 and the HHEX homeobox transcription factor. In addition, we are currently establishing conditional mouse models of leukemia that are induced by distinct "class II" mutations in order to study the genomic and epigenetic mechanisms of initiation, maintenance and relapse of the disease. |
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| Research within the Node | |
| Increasing evidence suggested that "class II" mutations also contribute to leukemogenesis by providing stem cell properties ("stemness") to early committed hematopoietic progenitor cells resulting in aberrant self-renewal and a block in differentiation. Previous work has proposed that these fusions might directly (or indirectly) interfere with posttranscriptional modification of the histone cores. As the chromatin state seems to define a stem cell state the question arises whether these fusions may contribute to leukemogenesis by "(re)-setting" an epigenetic stem cell mark in committed progenitor cells. Are there any significant differences in the chromatin state of normal versus leukemic stem cells? To delineate new targeted therapeutic avenues it is also critical to determine whether there may be a common epigenetic footprint in leukemic stem cells mediated by different leukemogenic mutations? | |
Adam M, Pogacic V, Bendit M, et al., Targeting PIM kinases impairs survival of hematopoietic cells transformed by kinase inhibitor-sensitive and kinase inhibitor-resistant forms of Fms-like tyrosine kinase 3 and BCR/ABL. CANCER RES, 66:3828.3835, 2006.
Pogacic V, Bullock AN, Fedorov O, et al., Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity CANCER RES, 67:6916-6924, 2007.
Jankovic D, Gorello P, Liu T, et al., Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia (AML). BLOOD 111: 5672-5682, 2008.
Grundler R, Brault L, Gasser C, et al., Dissection of serine/threonine PIM kinases in FLT3-ITD-induced leukemogenesis reveals PIM1 as regulator of CXCL12/CXCR4-mediated homing and migration. J EXP MED 206(9):1957-70 2009.