FLT3 Inhibitor AC220 Is a Potent Therapy for Myeloproliferative Disease in c-Cbl RING Finger Mutant Mice

• Published in: Blood 2011-11, Vol.118 (21), p.642-642
• Main Authors: Langdon, Wallace Y, Dagger, Samantha A, Taylor, Samuel J, Thien, Christine B F, Wikstrom, Matthew E
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V118.21.642.642

Abstract 642▪▪This icon denotes a clinically relevant abstract c-Cbl is a RING finger based E3 ubiquitin ligase that is highly expressed in hematopoietic cells where it directs the polyubiquitylation and degradation of protein tyrosine kinases. c-Cbl also functions as a multi-domain adaptor that recruits and activates proteins such as PI 3-kinase. Oncogenic forms c-Cbl that have lost E3 ligase show enhanced activity of these adaptor functions in addition to the inability to downregulate activated tyrosine kinases. c-Cbl mutations are found in patients with a range of myeloid malignancies that include myelodysplastic syndromes, chronic myelomonocytic leukaemia, juvenile myelomonocytic leukaemia, atypical chronic myeloid leukaemia and acute myeloid leukaemia. Sequencing has shown that the mutations are located in either the linker or RING finger domains and that these mutations abolish E3 ligase activity. Thus the development of leukemia is caused, at least in part, through the loss of this activity. To investigate c-Cbl associated malignancies we generated a mouse with a knockin mutation in the RING finger domain that develops a myeloproliferative disease (MPD) progressing to lethal leukemia. The mutation is a substitution of a cysteine for alanine in the RING finger at 379 (i.e. C379A) that disrupts c-Cbl's ability to function as an E3 ubiquitin ligase. The majority of the c-Cbl C379A mutant mice succumb within a year with markedly elevated white blood cell (WBC) counts, splenomegaly and extensive infiltrations of myeloid cells into peripheral organs. These mice therefore provide a pre-clinical model for studying myeloid malignancies associated with oncogenic forms of c-Cbl. We have found that hematopoietic progenitors from c-Cbl(C379A) mice have enhanced FLT3 signaling and an expanded population of FLT3high cells compared to WT and c-Cbl KO mice. When c-Cbl(C379A) mice are mated to FLT3 ligand KO mice the doubly mutant mice do not develop a severe MPD or leukemia and the FLT3high population is markedly suppressed. Thus targeting FLT3 may offer an effective therapy. AC220 is a FLT3 inhibitor that shows excellent potency, selectivity and pharmacokinetic properties and is currently being investigated in clinical trials treating patients with activating FLT3 mutations. In this study we examined the effects of treating c-Cbl(C379A) mice with AC220 to determine whether AC220 can prevent the development of myeloid malignancies associated with aberrant wild-type