Genetic instability in BCR-ABL1-transformed B cell lineage leukemia

• Applicant: Professor Dr. Markus Müschen
• Subject Area: Hematology, Oncology
• Term: from 2009 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 103441856

B cell lineage acute lymphoblastic leukemia (ALL) with the so-called Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase has a particularly poor prognosis. Ph+ ALL is typically treated with BCR-ABL1 kinase inhibitors such as Imatinib. The treatment response to Imatinib, however, is not durable and after a latency of only a few months, Ph+ ALL cells become drug-resistant and ALL relapses. In contrast to Ph+ ALL, long-term treatment of Ph+ chronic myeloid leukemia (CML) with Imatinib is effective and resistance develops only rarely, unless the disease progresses into B lymphoid blast crisis (CML-LBC). In most cases, acquired resistance to Imatinib in Ph+ ALL and CML-LBC can be attributed to somatic mutations within the BCR-ABL1 kinase domain, which compromise the efficacy of Imatinib. In preliminary experiments for this proposal, we show that AID is specifically expressed in B cell lineage clones of BCR-ABL1-driven leukemia (Ph+ ALL and CML-LBC). In these cells, AID functions as a mutator and thereby contributes to the drug-resistance typically observed in Ph+ ALL and CML-LBC. Based on these findings, our proposal addresses the question of(1) how AID contributes to genetic instability in Ph+ ALL (e.g. AID-specific deletions; Aim 1),(2) to which extent AID contributes to the progression of chronic phase CML to CML-LBC (outgrowth of B lymphoid subclones that carry advantageous mutations; Aim 2),(3) which factors cause aberrant expression of AID in Ph+ ALL and CML-LBC (Aim 3),(4) and whether AID-expressing clones in Ph+ ALL and CML-LBC can be specifically targeted in a prodrug based approach that takes advantage of the enzymatic activity of AID (Aim 4).Together, these four Aims will help to elucidate mechanisms of drug-resistance in Ph+ ALL and CML-LBC and propose a novel concept of targeted treatment Ph+ ALL and CML-LBC for pre-clinical evaluation.

• DFG Programme: Research Grants