New leukemia mutation offers therapeutic targets

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1. Mutations in the colony-stimulating factor 3 receptor (CSF3R) gene were found in a majority of samples of neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (CML). 

2. Different types of CSF3R mutations are associated with vulnerability to different therapeutics in vitro and potentially in vivo.  

Study Rundown: Aberrant kinases have been implicated in a number of cancers, and small molecule inhibitors of these kinases have proven to be useful therapeutics. Hypothesizing that there are undiscovered mutations that affect kinase activity in leukemia, the authors screened nearly 400 samples from leukemia patients for mutations in kinases and related genes.

The strength of this study is that the genetic screen is accompanied by functional analysis of the mutations identified. In this case, CSF3R mutations were identified in chronic neutrophilic leukemia (CNL) and atypical chronic myelogenous leukemia (CML). The authors teased apart functional differences in these mutations by challenging patient samples with panels of kinase inhibitors and kinase-specific small-interfering RNAs. As a proof-of-concept, they also demonstrated clinical improvement in one patient who received a kinase inhibitor matched to his type of CSF3R mutation.

Although CNL and atypical CML are rare leukemias, this work offers strong evidence that CSF3R mutations are functionally significant in these cancers and that JAK and SRC family-TNK2 kinase inhibitors should be pursued as therapeutics in clinical trials.

Click to read the study, published today in NEJM

Relevant Reading: CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia

In-Depth [genetic screening study]: Using deep sequencing, the authors screened 371 samples of hematologic cancers for mutations in 1862 genes, including all kinases and growth factor receptors. They found mutations in the growth factor receptor-encoding CSF3R gene in 16 out of 27 samples of chronic neutrophilic leukemia (CNL) or atypical chronic myelogenous leukemia (CML). Only 4 CSFR3 mutations were found in the other 344 samples of hematologic cancer.

The mutations in CSF3R were of two types. Samples with truncation mutations were inhibited by SRC family-TNK2 kinase inhibitors, but not JAK kinase inhibitors. Samples with membrane proximal mutations were inhibited by JAK kinase inhibitors, but not SRC family-TNK2 kinase inhibitors.

A patient with CNL positive for a membrane proximal mutation was treated with the JAK kinase inhibitor ruxolitinib and showed clinical improvement.

By Tomi Jun and Mitalee Patil

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