Die Bedeutung des Lymphozyten-Transkriptionsfaktors Interferon regulierender Faktor 4 in der Entstehung von präB Zell Leukämien der Maus
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Philipps-Universität Marburg
Abstract
B cell development in the bone marrow is the result of a tightly regulated interplay of intrinsic and extrinsic control mechanisms. Disruptions in this system can give rise to the
development of B cell progenitor acute lymphoblastic leukemia.
The aim of the present work was to characterise the causes of a spontaneous leukemic
disease in Irf4–/– mice. To this end, preleukemic alterations in the B cell progeny of healthy Irf4–/– mice was investigated. Both an impaired differentiation beyond the preBCR checkpoint as well as reduced adhesion to the bone marrow niche as a result of decreased sensitivity
to the chemotactic factor CXCL12 was observed. Both phenomena induced unchecked expression of the mutagenic enzyme AID. Irf4–/– leukemia was characterised by recurrent
Jak3 mutations, resulting in enhanced IL-7 sensitivity without granting complete cytokine
independency to leukemia cells. Treating mice with established Irf4–/– leukemia with the JAKinhibitor Ruxolitinib resulted in the preferential reduction of leukemia infiltration into solid
organs without a systemic effect on the leukemic burden in peripheral blood or bone marrow. Especially the reduction in leukemic meningeosis marked by clinical reductions in paralysis symptoms, is to be noted as of high translational importance. Comparisons between the
thus characterised Irf4–/– leukemia and the human disease spectrum yielded a striking resemblance to the Ph-like BCP-ALL entity. As, to this date, little is known about the causative pathomechanisms behind the disease, the insights portrayed in the present work
might be of importance for our understanding of Ph-like BCP-ALL.
In parallel, techniques for the overexpression of transcription factors were employed to address the potential reversibility of decreased suppressive capacities observed in mutated
Tregs.
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