Rearrangements of the MLL gene at chromosome 11q23 portend a poor prognosis in patients with acute leukemia. MLL rearrangements are found in 5-10% of acute leukemias and are particularly common both in babies with leukemia and in chemotherapy-associated secondary leukemia. New approaches to the treatment of MLL leukemia are warranted as increasingly aggressive therapy has yielded only modest improvements in survival. Reciprocal translocations at the MLL locus are heterogeneous, but the two most common translocation partners are the AF4 and AF9 genes. We previously demonstrated that AF4 and AF9 proteins form a multiprotein complex. Moreover, the protein complex can be disrupted in vitro and in vivo by small synthetic peptides that mimic the AF9 binding site of AF4. When exposed to one such peptide, designated PFWT, leukemia cell lines expressing MLL-AF4 or MLL-AF9 fusion genes undergo programmed cell death by necrosis. Importantly, no effect on bone marrow colony formation is observed at peptide concentrations that are toxic to leukemia cells. One possible explanation for these observations is that macromolecular complexes comprised of AF4 and AF9 chimeric proteins are crucial for the survival of t(4;11) and t(9;11) leukemia cells. By binding AF9 and disrupting MLL-AF4-AF9 (or MLL-AF9-AF4) protein complexes, PFWT inhibits MLL leukemias. This research project focuses on the role of the mutual interaction domains of AF4 and AF9 and will examine the requirement for binding of AF9 to AF4 or to Dot1 histone methyltransferase in leukemogenesis. By analyzing the contributions of specific proteins to the activity of chimeric oncoproteins, these studies are designed to reveal promising new approaches to treat MLL leukemia. We have devised the PFWT peptide as a prototype of molecules that block protein interactions critical to leukemia cell survival. However, we also hope to extend the impact of experimental tools to feasible treatment strategies. Thus, a highly substituted and more potent derivative of PFWT peptide, SPK- 107, will be tested in a mouse model of human MLL leukemia. These pre-clinical studies are intended to lay the groundwork for pharmaceutical drug development.
This research project focuses on a newly described molecule that is selectively toxic to leukemia cell lines with rearrangements of the MLL gene. MLL leukemias are resistant to therapy and innovative approaches to treatment are important. In addition to assessing the utility of a new treatment, experiments are anticipated to reveal unique and important features of the biology of MLL leukemias.
|Lokken, Alyson A; Achille, Nicholas J; Chang, Ming-Jin et al. (2014) Importance of a specific amino acid pairing for murine MLL leukemias driven by MLLT1/3 or AFF1/4. Leuk Res 38:1309-15|
|Barretto, Nisha N; Karahalios, Dean S; You, Dewen et al. (2014) An AF9/ENL-targted peptide with therapeutic potential in mixed lineage leukemias. J Exp Ther Oncol 10:293-300|
|Malik, Bhavna; Hemenway, Charles S (2013) CBX8, a component of the Polycomb PRC1 complex, modulates DOT1L-mediated gene expression through AF9/MLLT3. FEBS Lett 587:3038-44|
|Chang, Ming-Jin; Wu, Hongyu; Achille, Nicholas J et al. (2010) Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes. Cancer Res 70:10234-42|
|Lin, Jeffrey J; Hemenway, Charles S (2010) Hsp90 directly modulates the spatial distribution of AF9/MLLT3 and affects target gene expression. J Biol Chem 285:11966-73|
|Bennett, Cecily A; Winters, Amanda C; Barretto, Nisha N et al. (2009) Molecular targeting of MLL-rearranged leukemia cell lines with the synthetic peptide PFWT synergistically enhances the cytotoxic effect of established chemotherapeutic agents. Leuk Res 33:937-47|
|Palermo, Christine M; Bennett, Cecily A; Winters, Amanda C et al. (2008) The AF4-mimetic peptide, PFWT, induces necrotic cell death in MV4-11 leukemia cells. Leuk Res 32:633-42|