1 - Introduction:
Acute Myeloid Leukemia (AML) is characterized by a malignancy of cells in the myeloid lineage and caused by diverse genomic alterations, resulting in a heterogenous disease with varied response to conventional therapies1. Among the heterogenous makeup of AML, Monosomy7 (Mono7) is one of the most established poor prognostic markers in AML with over four decades of clinical outcome data from a variety of clinical trials and other studies2, 3, 4, 5. Mono7 is a rare event in pediatric AML resulting from the somatic copy number loss of chromosome 7; despite intensive and myeloablative therapies, outcomes for this subtype of AML remain dismal with no meaningful advances in therapy.
We recently reported the discovery of fusions involving the Anaplastic Tyrosine Kinase (ALK ) gene and its unique occurrence in Mono7 pediatric AML6. The ALK gene encodes a receptor tyrosine kinase, belonging to a family of protein kinases linked to unregulated cell growth, that is a key component in CNS development7. ALK is located on chromosome 2 (2p23) and chimeric ALK fusions have been frequently observed in cases of inversion 2, as described in Non-Small Cell Lung Cancer (NSLC), Anaplastic Large-Cell Lymphoma (ALCL), and Neuroblastoma8, 9. Additionally, ALK is integral to various molecular pathways involving proliferation and differentiation in cells leading to a unique connection betweenALK and tumorigenesis10. The genetic alterations described here involve Spectrin Beta Non-Erythrocytic 1 (SPTBN1 ), and RAN Binding Protein 2 (RANBP2 ), both of which are located on chromosome 2. While previously reported in adult AML and myelomonocytic leukemia, this report describes the first instance of SPTBN1-ALK and RANBP2-ALK in pediatric AML11, 12, 13.
ALK alterations in a variety of cancers have been observed to be susceptible to targeted therapy with various kinase inhibitors14, 15, 16. ALK positive relapsed/refractory ALCL, Neuroblastoma, and other solid tumors in children and young adults have been successfully treated with crizotinib: an FDA-approved kinase inhibitor17, 18, 19. Here we provide studies defining the functional consequence of these ALK fusions (ALKfus) demonstrating that these fusions are transforming alterations and cells harboring these fusions are sensitive to the ALK inhibitor crizotinib in a hematologic environment. These data support the potential role of crizotinib to therapeutically target this highly refractory cohort of Mono7 patients.