Childhood Cancer

You are here

Targeting ALK Fusions in Monosomy 7 AML

Fred Hutchinson Cancer Research Center
Makia Krysten Manselle
Grant Type: 
POST Program Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

Mentor: Soheil Meshinchi

As part of Target Pediatric AML (TpAML), discovery efforts that have sequenced over 2000 children and young adults with AML, we have discovered two novel (cryptic) fusions involving the anaplastic tyrosine kinase gene, a well-known receptor tyrosine kinase (RTK). These fusions, SPTBN1-ALK and RANBP2-ALK are uniquely expressed in 20% of patients with monosomy 7 (-7 AML), one of the most refractory subtypes of AML. I have experimentally verified expression of this fusion transcript and aim to define their functional biology and whether ALK fusions may provide a viable opportunity for therapeutic targeting with Crizotinib, an FDA-approved kinase inhibitor. Over the last 6 months, I have developed assays to confirm presence of ALK fusions in and correlated ALK fusions with highly overexpressed ALK transcript. In preparation for studying the functional consequence of these fusions, I have cloned the two ALK fusions and ready to continue studies into the role of these fusions in AML and whether Crizotinib might lead to cell death in cell lines transduced with ALK fusions. Several cell lines, including Baf3, Kasumi, and MV4-;11 cell lines will be transduced with the two fusion transcripts using retroviral transduction. Initial studies will include cellular proliferation of the parental and the transduced cells to determine the implications of the fusions in cell proliferation. IL3-dependent Baf3 cells will be studied for cytokine-independent cellular proliferation after transduction to determine whether ALK fusions lead to autonomous cell growth. Finally, parental and fusion-transduced cells will be treated with Crizotinib to determine the therapeutic potential of the ALK inhibitor in fusion-positive cells. The hope is that we will be able to mimic AML conditions and test for drug sensitivity and confirm whether or not ALK is truly a viable target for Crizotinib in this very high-risk AML population. 

Co-funded by: 
Northwestern Mutual Foundation