No abstract

Complexity of products and systems is increasing through digitalization, interdisciplinarity as well as high technology maturity and new business models. In consequence, new product development (NPD) projects need to manage and satisfy a large number of requirements from a broad range of stakeholders. Yet, NPD projects are often delayed due to requirement changes. In this paper, a new method for analyzing requirement change propagation is presented. The method is based on the assessment of requirement interrelations structured in a requirements structure matrix by a modified page-rank algorithm. By the method, a high number of strongly interrelated requirements can be analyzed in an efficient manner. Additionally, higher-level interrelations as well as the relative weights of requirements are also incorporated in the analysis. Hereby, an efficient holistic approach towards the analysis of requirement change propagation is proposed.

Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression, and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4C1013G) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic pathways. CXCR4 hyperactivation resulted in an expansion of transitional B1 lymphocytes, which represent the precursors of chronic lymphocytic leukemia (CLL). Indeed, CXCR4 hyperactivation led to a significant acceleration of disease onset and a more aggressive phenotype in the murine Eµ-TCL1 CLL model. Hyperactivated CXCR4 signaling cooperated with TCL1 to cause a distinct oncogenic transcriptional program in B cells, characterized by PLK1/FOXM1-associated pathways. In accordance, Eµ-TCL1;CXCR4C1013G B cells enriched a transcriptional signature from patients with Richter’s syndrome, an aggressive transformation of CLL. Notably, MYC activation in aggressive lymphoma was associated with increased CXCR4 expression. In line with this finding, additional hyperactive CXCR4 signaling in the Eµ-Myc mouse, a model of aggressive B-cell cancer, did not impact survival. In summary, we here identify CXCR4 hyperactivation as a co-driver of an aggressive lymphoma phenotype.