Yang Zhang1, Fang Wang1, Xue Chen1, Yu Zhang1, Mingyu Wang1, Hong Liu1, Panxiang Cao1, Xiaoli Ma1, Tong Wang1, Jianping Zhang2, Xian Zhang3, Peihua Lu4,5, Hongxing Liu1,5. 1. Division of Pathology and Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China. 2. Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China. 3. Department of Hematology, Hebei Yanda Lu Daopei Hospital, Langfang, China. 4. International Medical Center, Hebei Yanda Lu Daopei Hospital, Langfang, China. 5. Beijing Lu Daopei Institute of Hematology, Beijing, China.
Abstract
BACKGROUND: Mutations in the colony-stimulating factor 3 receptor (CSF3R) gene occur frequently in chronic neutrophilic leukemia and are rare in de novo acute leukemia. The objective of this study was to assess the incidence of CSF3R mutations in acute leukemia and their association with other genetic abnormalities. METHODS: Amplicon-targeted, next-generation sequencing of 58 genes was performed retrospectively on 1152 patients (acute myeloid leukemia [AML], n = 587; acute lymphoid leukemia [ALL], n = 565). Reverse transcriptase-polymerase chain reaction analysis was used to detect 35 leukemia-specific gene fusions. RESULTS: CSF3R mutations (26 patients) were detected in 3.6% (13 of 364 patients), 4.6% (8 of 175 patients), and 8.3% (4 of 48 patients) of those with de novo, relapsed, and secondary AML, respectively, and in 0.2% (1 of 565 patients) of those with ALL. In total, 9 distinct CSF3R mutations were detected. Membrane-proximal missense mutations and cytoplasmic truncations were identified as mutually exclusive. The proportion of patients who had French-American-British subtypes M2 and M4 in the CSF3R-mutated group was significantly greater than that in the CSF3R wild-type group for both the de novo AML cohort (P = .001) and the relapsed AML cohort (P = .024). All de novo and relapsed AMLs with CSF3R mutations were associated with genetic alterations in transcription factors, including RUNX1-RUNX1T1, CBFB-MYH11, double-mutated CCAAT/enhancer binding protein α (CEBPAdm), and NPM1 mutations; and core-binding factor gene abnormalities and CEBPAdm accounted for 90.5% (19 of 21 patients). CONCLUSIONS: CSF3R mutations are uncommon in AML; however, when they occur, they are often associated with core-binding factor gene abnormalities and CEBPAdm. An in-depth understanding of the interaction between these genetic alterations could facilitate a clearer understanding of the role of CSF3R mutations in AML development and may be used for disease classification, prognosis, and the development of targeted therapy.
BACKGROUND: Mutations in the colony-stimulating factor 3 receptor (CSF3R) gene occur frequently in chronic neutrophilic leukemia and are rare in de novo acute leukemia. The objective of this study was to assess the incidence of CSF3R mutations in acute leukemia and their association with other genetic abnormalities. METHODS: Amplicon-targeted, next-generation sequencing of 58 genes was performed retrospectively on 1152 patients (acute myeloid leukemia [AML], n = 587; acute lymphoid leukemia [ALL], n = 565). Reverse transcriptase-polymerase chain reaction analysis was used to detect 35 leukemia-specific gene fusions. RESULTS:CSF3R mutations (26 patients) were detected in 3.6% (13 of 364 patients), 4.6% (8 of 175 patients), and 8.3% (4 of 48 patients) of those with de novo, relapsed, and secondary AML, respectively, and in 0.2% (1 of 565 patients) of those with ALL. In total, 9 distinct CSF3R mutations were detected. Membrane-proximal missense mutations and cytoplasmic truncations were identified as mutually exclusive. The proportion of patients who had French-American-British subtypes M2 and M4 in the CSF3R-mutated group was significantly greater than that in the CSF3R wild-type group for both the de novo AML cohort (P = .001) and the relapsed AML cohort (P = .024). All de novo and relapsed AMLs with CSF3R mutations were associated with genetic alterations in transcription factors, including RUNX1-RUNX1T1, CBFB-MYH11, double-mutated CCAAT/enhancer binding protein α (CEBPAdm), and NPM1 mutations; and core-binding factor gene abnormalities and CEBPAdm accounted for 90.5% (19 of 21 patients). CONCLUSIONS:CSF3R mutations are uncommon in AML; however, when they occur, they are often associated with core-binding factor gene abnormalities and CEBPAdm. An in-depth understanding of the interaction between these genetic alterations could facilitate a clearer understanding of the role of CSF3R mutations in AML development and may be used for disease classification, prognosis, and the development of targeted therapy.
Authors: Katherine Tarlock; Todd Alonzo; Yi-Cheng Wang; Robert B Gerbing; Rhonda E Ries; Tiffany Hylkema; Jenny L Smith; Julia E Maxson; Soheil Meshinchi Journal: Blood Date: 2020-04-30 Impact factor: 22.113
Authors: David R Spiciarich; Stephen T Oh; Amy Foley; Seamus B Hughes; Michael J Mauro; Omar Abdel-Wahab; Richard D Press; Rosa Viner; Sarah L Thompson; Qiushi Chen; Parastoo Azadi; Carolyn R Bertozzi; Julia E Maxson Journal: Cancer Res Date: 2018-10-22 Impact factor: 12.701
Authors: Theodore P Braun; Cody Coblentz; Brittany M Curtiss; Daniel J Coleman; Zachary Schonrock; Sarah A Carratt; Rowan L Callahan; Breanna Maniaci; Brian J Druker; Julia E Maxson Journal: Proc Natl Acad Sci U S A Date: 2020-05-29 Impact factor: 11.205
Authors: Amy M Trottier; Lawrence J Druhan; Ira L Kraft; Amanda Lance; Simone Feurstein; Maria Helgeson; Jeremy P Segal; Soma Das; Belinda R Avalos; Lucy A Godley Journal: Blood Adv Date: 2020-10-27
Authors: Theodore P Braun; Mariam Okhovat; Cody Coblentz; Sarah A Carratt; Amy Foley; Zachary Schonrock; Brittany M Curtiss; Kimberly Nevonen; Brett Davis; Brianna Garcia; Dorian LaTocha; Benjamin R Weeder; Michal R Grzadkowski; Joey C Estabrook; Hannah G Manning; Kevin Watanabe-Smith; Sophia Jeng; Jenny L Smith; Amanda R Leonti; Rhonda E Ries; Shannon McWeeney; Cristina Di Genua; Roy Drissen; Claus Nerlov; Soheil Meshinchi; Lucia Carbone; Brian J Druker; Julia E Maxson Journal: Nat Commun Date: 2019-11-29 Impact factor: 17.694