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.