Chronic neutrophilic leukemia with JAK2 mutation: is it true chronic neutrophilic leukemia?
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ABSTRACT:
SUBMITTER: Gao J
PROVIDER: S-EPMC10567908 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
Publications
Chronic neutrophilic leukemia with JAK2 mutation: is it true chronic neutrophilic leukemia?
Gao Jiapei J Gao Junyin J Min Fengling F
Annals of hematology 20230731 11
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Project description:Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Recently, the World Health Organization guidelines have been updated to include CSF3R mutations as part of the diagnostic criteria for CNL. Because of the high prevalence of CSF3R mutations in CNL, it is tempting to think of this disease as being solely driven by this genetic lesion. However, recent additional genomic characterization demonstrates that CNL has much in common with other chronic myeloid malignancies at the genetic level, such as the clinically related diagnosis atypical chronic myeloid leukemia. These commonalities include mutations in SETBP1, spliceosome proteins (SRSF2, U2AF1), and epigenetic modifiers (TET2, ASXL1). Some of these same mutations also have been characterized as frequent events in clonal hematopoiesis of indeterminate potential, suggesting a more complex disease evolution than was previously understood and raising the possibility that an age-related clonal process of preleukemic cells could precede the development of CNL. The order of acquisition of CSF3R mutations relative to mutations in SETBP1, epigenetic modifiers, or the spliceosome has been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL. Understanding the complete landscape and chronology of genomic events in CNL will help in the development of improved therapeutic strategies for this patient population.
| S-EPMC5301820 | biostudies-literature
Project description:Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that includes only 150 patients described to date meeting the latest World Health Organization (WHO) criteria and the recently reported CSF3R mutations. The diagnosis is based on morphological criteria of granulocytic cells and the exclusion of genetic drivers that are known to occur in others MPNs, such as BCR-ABL1, PDGFRA/B, or FGFR1 rearrangements. However, this scenario changed with the identification of oncogenic mutations in the CSF3R gene in approximately 83% of WHO-defined and no monoclonal gammopathy-associated CNL patients. CSF3R T618I is a highly specific molecular marker for CNL that is sensitive to inhibition in vitro and in vivo by currently approved protein kinase inhibitors. In addition to CSF3R mutations, other genetic alterations have been found, notably mutations in SETBP1, which may be used as prognostic markers to guide therapeutic decisions. These findings will help to understand the pathogenesis of CNL and greatly impact the clinical management of this disease. In this review, we discuss the new genetic alterations recently found in CNL and the clinical perspectives in its diagnosis and treatment. Fortunately, since the diagnosis of CNL is not based on exclusion anymore, the molecular characterization of the CSF3R gene must be included in the WHO criteria for CNL diagnosis.
| S-EPMC4562747 | biostudies-literature
Project description:PurposeColony-stimulating factor-3 receptor (CSF3R)-T618I is a recurrent activating mutation in chronic neutrophilic leukemia (CNL) and to a lesser extent in atypical chronic myeloid leukemia (aCML) resulting in constitutive JAK-STAT signaling. We sought to evaluate safety and efficacy of the JAK1/2 inhibitor ruxolitinib in patients with CNL and aCML, irrespective of CSF3R mutation status.MethodsWe conducted a phase II study of ruxolitinib in 44 patients (21 CNL and 23 aCML). The primary end point was overall hematologic response rate (ORR) by the end of 6 continuous 28-day cycles for the first 25 patients enrolled. We considered a response as either partial (PR) or complete response (CR). We expanded accrual to 44 patients to increase our ability to evaluate secondary end points, including grade ≥ 3 adverse events, spleen volume, symptom assessment, genetic correlates of response, and 2-year survival.ResultsORR was 32% for the first 25 enrolled patients (8 PR [7 CNL and 1 aCML]). In the larger cohort of 44 patients, 35% had a response (11 PR [9 CNL and 2 aCML] and 4 CR [CNL]), and 50% had oncogenic CSF3R mutations. The mean absolute allele burden reduction of CSF3R-T618I after 6 cycles was greatest in the CR group, compared with the PR and no response groups. The most common cause of death is due to disease progression. Grade ≥ 3 anemia and thrombocytopenia were observed in 34% and 14% of patients, respectively. No serious adverse events attributed to ruxolitinib were observed.ConclusionRuxolitinib was well tolerated and demonstrated an estimated response rate of 32%. Patients with a diagnosis of CNL and/or harboring CSF3R-T618I were most likely to respond.
| S-EPMC7106977 | biostudies-literature
Project description:Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm defined by persistent, predominantly mature neutrophil proliferation, marrow granulocyte hyperplasia, and frequent splenomegaly. The seminal discovery of oncogenic driver mutations in CSF3R in the majority of patients with CNL in 2013 generated a new scientific framework for this disease as it deepened our understanding of its molecular pathogenesis, provided a biomarker for diagnosis, and rationalized management using novel targeted therapies. Consequently, in 2016, the World Health Organization (WHO) revised the diagnostic criteria for CNL to reflect such changes in its genomic landscape, now including the presence of disease-defining activating CSF3R mutations as a key diagnostic component of CNL. In this communication, we provide a background on the history of CNL, its clinical and hemopathologic features, and its molecular anatomy, including relevant additional genetic lesions and their significance. We also outline the recently updated WHO diagnostic criteria for CNL. Further, the natural history of the disease is reviewed as well as potential prognostic variables. Finally, we summarize and discuss current treatment options as well as prospective novel therapeutic targets in hopes that they will yield meaningful improvements in patient management and outcomes.
| S-EPMC5811432 | biostudies-literature
Project description:Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid neoplasms defined largely by morphologic criteria. The discovery of CSF3R mutations in aCML and CNL have prompted a more comprehensive genetic profiling of these disorders. These studies have revealed aCML to be a genetically more heterogeneous disease than CNL, however, several groups have reported that SETBP1 and ASXL1 mutations occur at a high frequency and carry prognostic value in both diseases. We also report a novel finding-our study reveals a high frequency of U2AF1 mutations at codon Q157 associated with CSF3R mutant myeloid neoplasms. Collectively, these findings will refine the WHO diagnostic criteria of aCML and CNL and help us understand the genetic lesions and dysregulated signaling pathways contributing to disease development. Novel therapies that emerge from these genetic findings will need to be investigated in the setting of a clinical trial to determine the safety and efficacy of targeting various oncogenic drivers, such as JAK1/2 inhibition in CSF3R-T618I-positive aCML and CNL. In summary, recent advances in the genetic characterization of CNL and aCML are instrumental toward the development of new lines of therapy for these rare leukemias that lack an established standard of care and are historically associated with a poor prognosis.
| S-EPMC5266507 | biostudies-literature
Project description: Not available
| S-EPMC5451352 | biostudies-literature
Project description:Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm that is genetically characterized by the absence of both the Philadelphia chromosome and BCR-ABL1 fusion gene and the high prevalence of mutations in the colony-stimulating factor 3 receptor (CSF3R). Additional disease-modifying mutations have been recognized in CNL samples, portraying a distinct mutational landscape. Despite the growing knowledge base on genomic aberrations, further progress could be gained from the availability of representative models of CNL. To address this gap, we screened a large panel of available leukemia cell lines, followed by a detailed mutational investigation with focus on the CNL-associated candidate driver genes. The sister cell lines CNLBC-1 and MOLM-20 were derived from a patient with CNL and carry CNL-typical molecular hallmarks, namely mutations in several genes, such as CSF3R, ASXL1, EZH2, NRAS, and SETBP1. The use of these validated and comprehensively characterized models will benefit the understanding of the pathobiology of CNL and help inform therapeutic strategies.
| S-EPMC8161829 | biostudies-literature
Project description:BackgroundThe 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.MethodsTo 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.ResultsWe identified activating mutations in the gene encoding the receptor for colony-stimulating 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.ConclusionsMutations 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.).
| S-EPMC3730275 | biostudies-literature
Project description: Not available
| S-EPMC7479634 | biostudies-literature
Project description:ObjectivesThis meta-analysis investigates the prognostic effect of SET binding protein 1 (SETBP1) mutations in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or chronic neutrophilic leukemia (CNL).MethodsEligible studies from Pubmed, Embase, and Web of Science were searched from database inception through April 2016. Hazard ratios (HRs) and 95% confidence interval (CI) of overall survival (OS) were pooled to calculate the prognostic significance of SETBP1 mutation in patients.ResultsA total of 12 studies with 2321 patients were included in this meta-analysis; 4 studies for MDS, 5 studies for CMML, and 3 studies for CNL. Pooled results suggested that MDS and CMML patients with SETBP1 mutations had a significantly poorer prognosis when compared with patients with wild-type SETBP1 (MDS: HR = 1.808, 95% CI (1.218-2.685), P = 0.001; CMML: HR = 2.223, 95% CI (1.493-3.308), P<0.001). SETBP1 mutations in CNL patients however, showed no significant effect on the overall survival (HR = 1.773, 95% CI (0.877-3.582), P = 0.111). The Begg's and Egger's tests did not show significant publication bias in any groups.ConclusionsCurrent evidence shows that SETBP1 mutation is associated with a poor prognosis in patients with MDS and CMML, but not in patients with CNL.
| S-EPMC5291491 | biostudies-literature