The Expanding Family of ALK-Mediated Malignancies in Childhood

Since the initial discovery of the NPM-ALK fusion gene in patients suffering from anaplastic large cell lymphoma, ALK rearrangements have been described in a variety of other tumor entities origination from various cell types. Non-small cell lung cancer, inflammatory myofibroblastic tumors, squamous cell carcinoma and – as most recently discovered – neuroblastoma are associated with gain-of-function mutations of the receptor tyrosine kinase ALK. Besides reviewing the pathobiology of aberrant ALK signalling, I will demonstrate that ALK is activated in a rare myeloproliferative disorder in children.

The patients showed several common characteristics like massive splenomegaly marked monocytosis, GM-CSG hypersensitivity, and failure to conventional AML-directed chemotherapy. All patients showed a monosomy 7 by cytogenetic analysis. The morphological appearance strongly reminded of features commonly seen in juvenile myelomonocytic leukemias (JMML). However, few clinical data differed from those of classical JMML, like older age at diagnosis, higher white blood count, and CNS positivity in at least one patient.

To experimentally proof that ALK overexpression results in GM-CSF hypersensitivity, we transduced murine hematopoietic progenitors with full-length ALK. Indeed, ALK overexpression caused GM-CSF hypersensitivity thus closely resembling the situation in patients with JMML.

In summary, I propose the term „atypical JMML-like myeloproliferation“ to characterize what I believe to be a novel form of myeloproliferation in children.

The report further broadens the spectrum of malignancies that may be targeted by an anti-ALK directed therapy.