Identifizierung genetischer Vulnerabilitäten bei der MLL-AF9-getriebenen akuten myeloischen Leukämie
Zusammenfassung der Projektergebnisse
A substantial proportion of adult AML cases are associated with balanced translocations of chromosome 11q23, and AML with t(9;11)(p22;q23) is recognized as a distinct entity by the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. On the molecular level, t(11q23) result in fusion of the MLL gene, which encodes a H3K4 methyltransferase, to a broad spectrum of partner genes. A unifying feature of MLL rearrangements is their ability to confer leukemia-initiating activity to hematopoietic progenitor cells through establishment of a distinct leukemogenic gene expression program, pointing to a common mechanism of transformation that could guide therapeutic development. Current treatment of MLL-rearranged leukemias is based on chemotherapy and, in select cases, allogeneic hematopoietic stem cell transplantation (HSCT) and results in low long-term survival rates. The outcome of patients with relapsed or refractory MLL-rearranged AML who are not candidates for intensive therapy is particularly dismal, with 2-year survival rates of less than 10%. Insights into MLL fusion-mediated leukemogenesis have spurred attempts to develop novel, molecular mechanism-based therapeutic strategies. However, these efforts have not yet translated into better therapies in the clinic, because mutant MLL is difficult to target directly and it is incompletely understood which of the cellular pathways altered by MLL rearrangement are critical for malignant transformation. We have discovered that MLL-rearranged AML cells are exceptionally reliant on non-canonical and non-redundant functions of the cell cycle regulator CDK6, and that CDK6 is rendered essential via direct targeting by MLL fusion proteins.1 CDK6 essentiality is also evident in a mouse model of highly aggressive, MLL fusion-driven AML and in primary human AML specimens harboring a variety of MLL rearrangements, supporting CDK6 as common target for therapy in MLL-rearranged AML. Of immediate translational relevance, the context-dependent effects of lowering CDK6 expression, which are mediated through enhanced myeloid differentiation in vitro and in vivo, are closely phenocopied by treatment with the small-molecule CDK4/6 inhibitor palbociclib, which is already undergoing clinical evaluation in other malignancies. Based on the unmet clinical need and the preclinical rationale developed in this project, we have launched an investigator-initiated phase 1b/2a clinical trial to evaluate the efficacy of palbociclib in patients with MLL-rearranged AML who are not candidates for intensive chemotherapy and allogeneic HSCT (AMLSG 23-14, ClinicalTrials.gov Identifier NCT02310243). Of particular translational relevance, co-clinical results emerging from the laboratory will be validated by interrogating samples from patients enrolled on the concurrent clinical trial. This provides a unique opportunity not only to anticipate the results of the ongoing clinical trial, but also to generate clinically relevant hypotheses that can inform the analysis and design of future clinical investigations.
Projektbezogene Publikationen (Auswahl)
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Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. American Society of Hematology Annual Meeting 2013, Abstract 62216
Placke T, Faber K, Nonami A, Putwain SL, Salih HR, Sykes SM, Root DE, Barbie DA, Hahn WC, Milsom MD, Scholl C, Fröhling S
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Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Annual Congress of the European Hematology Association 2014, Abstract 5991
Placke T, Faber K, Nonami A, Putwain S, Salih H, Heidel F, Krämer A, Root D, Barbie D, Armstrong S, Hahn W, Huntly B, Sykes S, Milsom M, Scholl C, Fröhling S
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Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 124:13-23, 2014
Placke T, Faber K, Nonami A, Putwain SL, Salih HR, Heidel FH, Krämer A, Root DE, Barbie DA, Krivtsov AV, Armstrong SA, Hahn WC, Huntly BJ, Sykes SM, Milsom MD, Scholl C, Fröhling S
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CDK4/6 inhibitor palbociclib for treatment of KMT2A-rearranged acute myeloid leukemia: interim analysis of the AMLSG 23-14 trial. American Society of Hematology Annual Meeting 2016, Abstract 94897
Fröhling S, Agrawal M, Jahn N, Fransecky L, Baldus C, Wäsch R, Lübbert M, Walter G, Jensen P, Scholl C, Habdank M, Döhner K, Döhner H, Schlenk RF
