Reprogramming of myeloid progenitors by the BCR-ABL oncogene

• Main Author: Bheeshmachar, Geetha
• Other Authors: Laslo, Peter
• Published: University of Leeds 2017
• Subjects: 610
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.739770

The constitutive tyrosine kinase activity of the BCR-ABL oncogene is central for the pathogenesis of chronic myeloid leukaemia (CML). Clinical treatment of CML with the kinase inhibitor Imatinib Mesylate (IM) is a fundamental success demonstrating disease addiction upon BCR-ABL activity. However, 15-20% of CML patients develop drug resistance leading to patient fatality. The most studied mechanism of IM-resistance is point mutations within the kinase domain of BCR-ABL. However, these account for ~40% of patients crafting the challenge in understanding how leukaemic cells can survive in the absence of BCR- ABL activity. To address this issue, a preclinical model of CML drug resistance was established using KCL22 cells (Chapter 3). Single cell clones were generated and drug resistant derivatives established which had (i) no mutations within BCR-ABL and (ii) functional IM pharmacokinetics with reduction in the phosphorylation of STAT5 and CrkL. Being kinase-independent, are other domains of BCR-ABL compensating to maintain the leukaemic state or is BCR-ABL now redundant? To address this, the consequence of BCR-ABL depletion was explored (Chapter 4). In contrast to the original parental KCL22 cells, the drug-resistant clones continued to survive and expand upon the loss of BCR-ABL, supporting the proposal of ‘oncogene independence’ as a novel mechanism to escape drug targeting. Genome-wide expression analysis identified the induction of the RUNX1 transcription factor upon drug resistance. As RUNX1 is deregulated is several haematological malignancies, its potential role in drug resistant CML was explored (Chapter 5). Targeting of RUNX1 within drug resistant cells resulted in the failure of these cells to grow associated with the acquisition of a macrophage-like phenotype. The work herein identifies oncogene independence as a novel mechanism for establishing drug resistant CML with RUNX1 functioning as new oncogenic driver to compensate for the loss of BCR-ABL and presenting itself as a new therapeutic target.