Identifying the Genetic Basis of Adult AMKL
- To perform high throughput sequencing of a set of megakaryocyte specific transcription
factors, tyrosine kinases, and Src kinases in DNA isolated from bone marrow specimens
of adults with acute megakaryoblastic leukemia (AMKL).
- To assay the ability of Src kinase inhibitors (SU6656, dasatinib) to induce
differentiation of AMKL blasts in these patients.
OUTLINE: DNA from previously collected bone marrow samples are sequenced to analyze genes
associated with transcription factors (GATA1, GATA2, SCL, FOG-1, ETS1, ETS2, ERG, FLI-1,
GABP, HOXA11, NF-E2, and RUNX1), tyrosine kinases (JAK2, JAK3, and c-MPL), and Src family
kinases (LYN, FYN, and HCK) and compared with control DNA. Using bioinformatics, gene
alterations are compared to known polymorphisms and subsequent changes in the amino acid
sequence of the encoded protein. Subsequent assays assess the effect on proliferation and
differentiation and in vitro studies evaluate the consequences of mutations on transcription
factor and kinase activity abilities. The effect of SU6656 and dasatinib on cell death and
polyploidization is evaluated by flow cytometry and compared with control DNA.
Correlation of gene mutations with adult acute megakaryoblastic leukemia (AMKL)
John Crispino, PhD
Robert H. Lurie Cancer Center