Murine Retrovirally-Transduced Bone Marrow Engraftment Models of MLL-Fusion-Driven Acute Myelogenous Leukemias (AML).

MLL-rearranged leukemia represents approximately 5% to 10% of adult acute myelogenous leukemia (AML) and nearly half of all infant/pediatric acute leukemia cases. These leukemias have a poor prognosis, and there are no approved therapeutic options. The rearrangement in the MLL gene leads to aberrant expression of MLL-fusion proteins. These are transforming in murine bone marrow and, in particular, on stem cells and myeloid progenitors derived from bone marrow or fetal liver. The commonality of the MLL fusions is the in-frame fusion of 8 to 11 N-terminal exons of MLL1 (KMT2a) with the C-terminus of a partner fusion gene. Currently, over 80 different fusion partners are known. The protocols detailed in this unit focus on bone marrow-derived models only, using one particular MLL fusion, MLL-AF9. These models have proven effective for drug screening to predict clinical response. © 2017 by John Wiley & Sons, Inc.

Stubbs MC ，Krivtsov AV 《-》

Hematopoietic transformation in the absence of MLL1/KMT2A: distinctions in target gene reactivation.

Chen Y ，Ernst P 《-》

Learning from mouse models of MLL fusion gene-driven acute leukemia.

5-10% of human acute leukemias carry chromosomal translocations involving the mixed lineage leukemia (MLL) gene that result in the expression of chimeric protein fusing MLL to >80 different partners of which AF4, ENL and AF9 are the most prevalent. In contrast to many other leukemia-associated mutations, several MLL-fusions are powerful oncogenes that transform hematopoietic stem cells but also more committed progenitor cells. Here, I review different approaches that were used to express MLL fusions in the murine hematopoietic system which often, but not always, resulted in highly penetrant and transplantable leukemias that closely phenocopied the human disease. Due to its simple and reliable nature, reconstitution of irradiated mice with bone marrow cells retrovirally expressing the MLL-AF9 fusion became the most frequently in vivo model to study the biology of acute myeloid leukemia (AML). I review some of the most influential studies that used this model to dissect critical protein interactions, the impact of epigenetic regulators, microRNAs and microenvironment-dependent signals for MLL fusion-driven leukemia. In addition, I highlight studies that used this model for shRNA- or genome editing-based screens for cellular vulnerabilities that allowed to identify novel therapeutic targets of which some entered clinical trials. Finally, I discuss some inherent characteristics of the widely used mouse model based on retroviral expression of the MLL-AF9 fusion that can limit general conclusions for the biology of AML. This article is part of a Special Issue entitled: The MLL family of proteins in normal development and disease edited by Thomas A Milne.

Schwaller J 《-》

MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment.

Stubbs MC ，Kim YM ，Krivtsov AV ，Wright RD ，Feng Z ，Agarwal J ，Kung AL ，Armstrong SA ... -  《-》

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia.

Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins.

Baker A ，Gregory GP ，Verbrugge I ，Kats L ，Hilton JJ ，Vidacs E ，Lee EM ，Lock RB ，Zuber J ，Shortt J ，Johnstone RW ... -  《-》