OncogenicCSF3RMutations in Chronic Neutrophilic Leukemia and Atypical CML

Abstract

BACKGROUND The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1–negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative– myelodysplastic overlap neoplasms. METHODS To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase–specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies. RESULTS We identified activating mutations in the gene encoding the receptor for colonystimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family–TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib. CONCLUSIONS Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.)

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

“…These mutations are common in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) and are uncommon in RARS-T [15,16].…”

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

“…The majority (8 of 9) of patients ( 90%) classified as CNL had CSF3R mutations. In comparison, 45% (8 of 18 cases) classified as aCML or "aCML favored over CNL", were carried a CSF3R mutation [1]. Both types of mutations were shown to possess in vitro transforming capacity which is mediated via different downstream signaling pathways.…”

“…A landmark publication by Maxson et al ushered in a new vision regarding the pathogenesis of CNL [1]. Based on the hypothesis that CNL or aCML (both considered neutrophilic BCR-ABL-negative leukemias) may be driven by oncogenes sensitive to small-molecule kinase inhibitors, as classically be demonstrated in other MPN, deep sequencing of the coding regions of over 1800 genes representing potential targets from primary cells from such patients was performed [1].…”

“…An unexpectedly high frequency of mutations in the CSF3R were found in 59% (16 of 27) patients with CNL and aCML, compared to only 1% of patients with AML (n 5 292). Two types of mutations were found; most were in the membrane proximal region which mediates proliferative and survival signals: CSF3R T618I (n 5 12) and CSF3R T615A (n 5 2) [1,9,10]. These occurred alone or in association with nonsense mutations that truncate cytoplasmic tail (a region important in transduction of maturation and suppression of proliferation) [1,9,10].…”

“…Both types of mutations were shown to possess in vitro transforming capacity which is mediated via different downstream signaling pathways. Specifically, the JAK-STAT (activated by membrane proximal mutations) and the SRC family-TNK2 kinase (activated by truncation mutations) pathways were involved, resulting in differential sensitivity to kinase inhibitors, such as ruxolitinib and dasatinib, respectively [1]. Taking these observations to immediate clinical relevance, these investigators reported that a CNL patient carrying CSF3R T618I, whose leukemia cells exhibited sensitivity to ruxolitinib in vitro, who achieved a dosedependent clinical response (reduction in the neutrophil and normalization of the platelet counts), with this drug [1].…”