The role of the CGRP-CALCRL axis in AML

Acute myeloid leukemia (AML) is a cancer that affects certain types of blood cells and their progenitors in the bone marrow. Its incidence increases with age. AML can be cured in some younger patients, but is fatal in the majority of cases. Like other malignant diseases, AML is caused by aberrations affecting the structure and/or the activity (expression) of certain genes. Alterations in numerous different genes can lead to AML, but certain recurrent patterns allow predictions about the course of disease, thereby informing therapeutic decisions. The detailed characterization of such aberrations has recently led to the development of novel, targeted therapeutics. These facilitate a more effective treatment with fewer side effects, but are approved only for defined subgroups of patients. Classical chemotherapy, which has been in use for decades, therefore remains the most important pillar of treatment. In the majority of patients, chemotherapy leads to disease remission, which, however, is frequently followed by disease recurrence (relapse). Relapse is caused by leukemic stem cells (LSCs) a population of cells that divide rarely, survive chemotherapy, and grow out to give rise to rapidly dividing AML cells. Relapsed AML responds to further chemotherapy hardly if at all, and therefore is usually fatal. Like leukemogenesis, the emergence of relapse and the associated therapy resistance are due to gene aberrations. However, in contrast to leukemogenic gene alterations, those associated with relapse have not been studied intensely so far. In previous work, we could show that the expression of CALCRL, a gene encoding a receptor protein, was upregulated at relapse of AML compared to diagnosis. Moreover, higher CALCRL levels at diagnosis correlated with a poorer response to chemotherapy. Initial functional experiments showed that activation of CALCRL by CGRP, a protein naturally binding to CALCRL, promotes LSC properties and chemotherapy resistance of AML cells. The current project builds on these findings, intending to take them further towards a potential therapeutic application of CGRP-CALCRL inhibitors in AML. To this end, mouse models, in which AML is caused by genetic changes analogous to those observed in human AML, will be used. In these models, the expression of Calcrl will be manipulated using state of the art molecular biology methods. Furthermore, treatment with the CGRP-CALCRL inhibitor olcegepant will be applied. The impact of these interventions on AML characteristics, specifically its response to chemotherapy and LSC properties, will be investigated. These studies will advance our understanding of the role of the CGRP-CALCRL axis in chemotherapy resistance and LSC properties of AML, and may lay a foundation for the therapeutic use of inhibitors of this axis in AML therapy.