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Gilliland awarded $14m to study genetic basis of leukemias

DF/HCC Member D. Gary Gilliland, MD, PhD (BWH) has successfully renewed his funding with the NCI to study the genetic basis of human leukemias and to develop therapeutic approaches based on these insights. Gilliland will receive $14m in total costs over five years. The P01, entitled "Novel Therapeutic Strategies in Human Myeloid Leukemias," consists of five projects:

Tyrosine kinase oncogenes in acute myeloid leukemias
James Griffin, MD (DFCI)

Project One: This project will continue to focus on tyrosine kinases mutated in myeloid leukemias, specifically to continue efforts to understand how to optimally target mutant FLT3 and two other tyrosine kinases, KIT and JAK2. The major focus of the project is on FLT3, specifically to test the hypothesis that combination targeted therapy for AML has more value than the use of a sole kinase inhibitor, develop high affinity inhibitors and study resistance mechanisms in hopes of  better understanding how to design the next generation of FLT3 kinase inhibitor trials. For KIT, models will be generated to assess their potential value in AML therapy. Finally, a third set of tyrosine inhibitors including JAK2 that are found to be mutated  in many patients with myeloproliferative disorders will be tested and compared in an effort to explore the therapeutic targeting of kinases in preclinical models with the goal of developing clinical trials.

Murine models of myeloid leukemias
D. Gary Gilliland, MD, PhD (BWH)

Project Two: This project will move forward with additional studies of the role of FLT3-ITD in leukemogenesis using conditional knock-out alleles. The three specific aims are: 1) to analyze the in vivo activity of FLT3-ITD and activation loop alleles, and understand the relative predilection of FLT3-ITD for myeloid lineage disease, and of FLT3 activation loop alleles for lymphoid disease; 2) explore cooperating effects of these accurate genotypic models of FLT3-ITD mediated disease through crosses with several complementing alleles, including C/EBPalpha and MLL fusions, and pursue recent findings that suggest retroviral FLT3-ITD integration sites may contribute to the pathogenesis of AML in the Cathepsin G PML-RARalpha model of cooperativity; and 3) develop murine models of myeloproliferative disease mediated by the JAK2V617F allele that has recently been identified, and use these models to test novel JAK2 inhibitors for development of clinical trials.

Oncogenesis and myeloid transcription factors in AML
Daniel Tenen, MD (BIDMC)

Project Three: The goal of this project is to better understand the mechanisms involved in leukemia by understanding the effect of various leukemia oncogenes on the transcription factors which regulate normal myeloid development from stem cells. Specific aims are: 1) to investigate the effects of PML/RAR alpha on C/EBPa, and the response of C/EBP beta to all trans retinoic acid (ATRA); 2) develop mouse models which combine the loss of C/EBPa and tyrosine kinases in development of AML; and 3) investigate the pathways between FLT3 activation, C/EBPa phosphorylation, and AML.

MLL fusion genes in myeloid and lymphoid leukemias
Scott Armstrong, MD, PhD (CHB)

Project Four: Using a murine model system of MLL-AF9 induced AML, a hematopoietic stem cell associated gene expression program activated in granulocyte macrophage progenitors during their conversion to leukemia stem cells (LSC) has been recently identified. In these studies, there was also noted a repression of cebp/a as a component of the MLL-AF9 induced program. Specfic aims for this project are: 1) to assess specific genes found highly expressed in LSC and perform a high-throughput screen to identify small molecules that reverse the LSC program; 2) work with members of project three to interrogate the role of cebp/a in MLL-rearranged leukemia; and 3) work with members of project one and two to develop a conditional murine model of MLL-AF4 induced leukemia and assess the potential for cooperation with mutant FLT3 alleles during leukemogenesis.

Clinical trials in myeloid malignancies
Richard Stone, MD (DFCI)

Project Five: In the past, we have led two studies combining FLT3 with the chemotherapy used in patients with newley diagnosed AML. The specific aims of this project will be to: 1) expand these FLT3 plus chemotherapy studies with a definite phase III study of standard chemotherapy +/- PKC412 and perform ancillary studies to determine the potential mechanisms of FLT3 resistance; and 2) perform clinical trials to test promising combinations in patients with mutant FLT3 AML.