Differential Implications of CSF3R Mutations in t(8;21) and CEBPA Double Mutated Acute Myeloid Leukemia

Wang, Biao; Wen, Li; Wang, Zheng; Chen, Suning; Qiu, Huiying

doi:10.1016/j.clml.2021.11.013

Cited by 3 publications

(3 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, somatic mutations clustering around the transmembrane region and intracellular domain of CSF3R have been described in the novo AML, being more frequent in AML with t(8;21)(q22;q22.1) and in AML with biallelic mutation of CEBPA . 57 , 58 , 59 The variant we found in CSF3R (c.296_299delTCTC, p.Leu99fs) causes a truncating protein at residue 103, located at the beginning of the extracellular domain. To date, it has not been demonstrated that heterozygote carriers of mutations affecting the extracellular domain of CSF3R, as could be family members of SCN patients, have an increased risk for developing AML, although the number of such patients is very low.…”

Section: Discussionmentioning

confidence: 85%

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

et al. 2023

View full text Add to dashboard Cite

Germline predisposition in acute myeloid leukemia (AML) has gained importance in recent years due to a non-negligible frequency and impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germline variants (GV) in 288 genes related to cancer predisposition in 47 patients with available paired tumor-normal material, namely bone marrow stroma cells (BMSC, n=29), post-remission bone marrow (PRBM, n=17) and saliva (n=1). These patients correspond to two broad AML categories with heterogeneous genetic background (AML myelodysplasia-related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia nor strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, six affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41 and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21 and CSF3R). We did not find differences in clinical characteristics nor outcome between GV carriers vs non-carriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.

show abstract

Section: Discussionmentioning

confidence: 85%

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

et al. 2023

View full text Add to dashboard Cite

show abstract

“…72 Later studies supported the lower frequency of CSF3R mutations in aCML (typically <10-20%, though ranging from 0 to 40% 8 ), and confirmed their high prevalence in WHO-defined CNL (80-100% of patients). 7,36,114,115 It is of note that CSF3R mutations are uncommon in acute myeloid leukemia (AML) (typically reported <3-4%) 116,117 ; however, when present, they are often associated with core-binding factor gene abnormalities and double-mutated CEBPA, the significance of which remains unclear. 118 Genotype variants may represent non-deleterious SNPs with genetic analysis of nonhematopoietic tissues confirming their germline origin.…”

Section: Csf3r Mutationsmentioning

confidence: 99%

Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management

Szuber,

Orazi,

Tefferi

2024

American J Hematol

View full text Add to dashboard Cite

Chronic neutrophilic leukemia (CNL) is a rare BCR::ABL1‐negative myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis and bone marrow granulocyte hyperplasia. Atypical chronic myeloid leukemia (aCML) (myelodysplastic “[MDS]/MPN with neutrophilia” per World Health Organization [WHO]) is a MDS/MPN overlap disorder featuring dysplastic neutrophilia and circulating myeloid precursors. Both manifest with frequent hepatosplenomegaly and less commonly, bleeding, with high rates of leukemic transformation and death. The 2022 revised WHO classification conserved CNL diagnostic criteria of leukocytosis ≥25 × 109/L, neutrophils ≥80% with <10% circulating precursors, absence of dysplasia, and presence of an activating CSF3R mutation. ICC criteria are harmonized with those of other myeloid entities, with a key distinction being lower leukocytosis threshold (≥13 × 109/L) for cases CSF3R‐mutated. Criteria for aCML include leukocytosis ≥13 × 109/L, dysgranulopoiesis, circulating myeloid precursors ≥10%, and at least one cytopenia for MDS‐thresholds (ICC). In both classifications ASXL1 and SETBP1 (ICC), or SETBP1 ± ETNK1 (WHO) mutations can be used to support the diagnosis. Both diseases show hypercellular bone marrow due to a granulocytic proliferation, aCML distinguished by dysplasia in granulocytes ± other lineages. Absence of monocytosis, rare/no basophilia, or eosinophilia, <20% blasts, and exclusion of other MPN, MDS/MPN, and tyrosine kinase fusions, are mandated. Cytogenetic abnormalities are identified in ~1/3 of CNL and ~15–40% of aCML patients. The molecular signature of CNL is a driver mutation in colony‐stimulating factor 3 receptor—classically T618I, documented in >80% of cases. Atypical CML harbors a complex genomic backdrop with high rates of recurrent somatic mutations in ASXL1, SETBP1, TET2, SRSF2, EZH2, and less frequently in ETNK1. Leukemic transformation rates are ~10–25% and 30–40% for CNL and aCML, respectively. Overall survival is poor: 15–31 months in CNL and 12–20 months in aCML. The Mayo Clinic CNL risk model for survival stratifies patients according to platelets <160 × 109/L (2 points), leukocytes >60 × 109/L (1 point), and ASXL1 mutation (1 point); distinguishing low‐ (0–1 points) versus high‐risk (2–4 points) categories. The Mayo Clinic aCML risk model attributes 1 point each for: age >67 years, hemoglobin <10 g/dL, and TET2 mutation, delineating low‐ (0–1 risk factor) and high‐risk (≥2 risk factors) subgroups. Management is risk‐driven and symptom‐directed, with no current standard of care. Most commonly used agents include hydroxyurea, interferon, Janus kinase inhibitors, and hypomethylating agents, though none are disease‐modifying. Hematopoietic stem cell transplant is the only potentially curative modality and should be considered in eligible patients. Recent genetic profiling has disclosed CBL, CEBPA, EZH2, NRAS, TET2, and U2AF1 to represent high‐risk mutations in both entities. Actionable mutations (NRAS/KRAS, ETNK1) have also been identified, supporting novel agents targeting involved pathways. Preclinical and clinical studies evaluating new drugs (e.g., fedratinib, phase 2) and combinations are detailed.

show abstract

“…65 Later studies corroborated the lower mutational frequency of CSF3R mutations in aCML, which ranges from 0% to 40%, and confirmed the high prevalence of CSF3R mutations in WHO-defined CNL (80%-100% of patients). 30,103,104 It is of note that CSF3R mutations are uncommon in AML (typically reported <3%-4%), 105,106 however, when present, they are often associated with core-binding factor gene abnormalities and double-mutated CEBPA, 107 with the significance of this association remaining unclear.…”

Section: Csf3r Mutations In Cnl: a Biological Unifying Featurementioning

confidence: 99%

Chronic neutrophilic leukemia: 2022 update on diagnosis, genomic landscape, prognosis, and management

2022

View full text Add to dashboard Cite

Disease Overview: Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly.The 2013 seminal discovery of oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL not only established its molecular pathogenesis but provided a diagnostic biomarker and rationale for pharmacological targeting.Diagnosis: In 2016, the World Health Organization (WHO) recognized activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 Â 10 9 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN.Management: There is currently no standard of care for management of CNL, due in large part to the rarity of disease and dearth of formal clinical trials. Most commonly used therapeutic agents include conventional oral chemotherapy (e.g., hydroxyurea), interferon, and Janus kinase (JAK) inhibitors, while hematopoietic stem cell transplant remains the only potentially curative modality.Disease Updates: Increasingly comprehensive genetic profiling in CNL, including new data on clonal evolution, has disclosed a complex genomic landscape with additional mutations and combinations thereof driving disease progression and drug resistance.Although accurate prognostic stratification and therapeutic decision-making remain challenging in CNL, emerging data on molecular biomarkers and the addition of newer agents, such as JAK inhibitors, to the therapeutic arsenal, are paving the way toward greater standardization and improvement of patient care.

show abstract

Differential Implications of CSF3R Mutations in t(8;21) and CEBPA Double Mutated Acute Myeloid Leukemia

Cited by 3 publications

References 42 publications

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management

Chronic neutrophilic leukemia: 2022 update on diagnosis, genomic landscape, prognosis, and management

Contact Info

Product

Resources

About