title: Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia.
abstract: Severe congenital neutropenia (SCN) is a BM failure syndrome with a high risk of progression to acute myeloid leukemia (AML). The underlying genetic changes involved in SCN evolution to AML are largely unknown. We obtained serial hematopoietic samples from an SCN patient who developed AML 17 years after the initiation of G-CSF treatment. Next- generation sequencing was performed to identify mutations during disease progression. In the AML phase, we found 12 acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, co-occurred in a subpopulation of progenitor cells already in the early SCN phase. This population expanded over time, whereas clones harboring only CSF3R mutations disappeared from the BM. The other 9 mutations were only apparent in the AML cells and affected known AML-associated genes (RUNX1 and ASXL1) and chromatin remodelers (SUZ12 and EP300). In addition, a novel CSF3R mutation that conferred autonomous proliferation to myeloid progenitors was found. We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development. The sequential gain of 2 CSF3R mutations implicates abnormal G-CSF signaling as a driver of leukemic transformation in this case of SCN.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Renée
authors.initials: R
authors.lastname: Beekman
authors.forename: Marijke G
authors.initials: MG
authors.lastname: Valkhof
authors.forename: Mathijs A
authors.initials: MA
authors.lastname: Sanders
authors.forename: Paulette M H
authors.initials: PM
authors.lastname: van Strien
authors.forename: Jurgen R
authors.initials: JR
authors.lastname: Haanstra
authors.forename: Lianne
authors.initials: L
authors.lastname: Broeders
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Geertsma-Kleinekoort
authors.forename: Anjo J P
authors.initials: AJ
authors.lastname: Veerman
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Roel G
authors.initials: RG
authors.lastname: Verhaak
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
mesh_terms: D000328:Adult; D001853:Bone Marrow / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009503:Neutropenia / Q000150:complications / Q000151:congenital / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D016179:Granulocyte Colony-Stimulating Factor