Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies

Abstract

Colony-stimulating factor 3 receptor (CSF3R) encodes the receptor for granulocyte colony-stimulating factor (G-CSF), a cytokine vital for granulocyte proliferation and differentiation. Acquired activating heterozygous variants in CSF3R are the main cause of chronic neutrophilic leukemia, a hyperproliferative disorder. In contrast, biallelic germ line hypomorphic variants in CSF3R are a rare cause of severe congenital neutropenia, a hypoproliferative condition. The impact of heterozygous germ line CSF3R variants, however, is unknown. We identified CSF3R as a new germ line hematologic malignancy predisposition gene through analysis of 832 next-generation sequencing tests conducted in 632 patients with hematologic malignancies. Among germ line CSF3R variants, 3 were abnormal in functional testing, indicating their deleterious nature. p.Trp547* was identified in 2 unrelated men with myelodysplastic syndromes diagnosed at 76 and 33 years of age, respectively. p.Trp547* is a loss-of-function nonsense variant in the extracellular domain that results in decreased CSF3R messenger RNA expression and abrogation of CSF3R surface expression and proliferative responses to G-CSF. p.Ala119Thr is a missense variant found in 2 patients with multiple myeloma and acute lymphoblastic leukemia, respectively. This variant is located between the extracellular immunoglobulin-like and cytokine receptor homology domains and results in decreased G-CSF sensitivity. p.Pro784Thr was identified in a 67-year-old man with multiple myeloma. p.Pro784Thr is a missense variant in the cytoplasmic domain that inhibits CSF3R internalization, producing a gain-of-function phenotype and G-CSF hypersensitivity. Our findings identify germ line heterozygous CSF3R variants as risk factors for development of myeloid and lymphoid malignancies.

Leukaemic evolution of rare donor CSF3R germline mutation after umbilical cord blood transplant

“…The CSF3R W547X observed in this patient occurs outside of the known mutational hotspot in the intracytoplasmic domain that inhibits the receptor signalling in SCN, and is distinct from the activating mutations observed in CNL or AML. A recent report identified germline CSF3R W547X in two MDS patients 2 . The first case was a 74‐year‐old man presenting with therapy‐related MDS.…”

“…demonstrated that the BaF3 cell line transfected with a vector containing CSF3R W547X cDNA experience a strong decrease in proliferative potential following withdrawal of IL‐3, when compared with overexpression of wild‐type CSFR3 . Mutant transfected cells also had a decrease in G‐CSFR cell surface expression that was the result of both non‐sense mediated decay and secretion of a truncated form of the receptor 2 …”

“…Molecular analysis of UCB2 showed a mutation in the extracellular domain of CSF3R (CSF3R:NM_156039:exon13:c.G1640A:p.W547X) (VAF 47.6%) which results in a monoallelic loss of function of CSF3R 2 …”

Lessons From Pediatric MDS: Approaches to Germline Predisposition to Hematologic Malignancies

“… f Biallelic hypomorphic mutations in CSF3R are associated with severe congenital neutropenia where no cases of MDS or AML have been reported. Heterozygous CSF3R germline mutations have been associated with single kindred with MDS, MM and ALL ( 85 ). …”

“…f Biallelic hypomorphic mutations in CSF3R are associated with severe congenital neutropenia where no cases of MDS or AML have been reported. Heterozygous CSF3R germline mutations have been associated with single kindred with MDS, MM and ALL (85). g Increased risk of MDS and AML has been reported in patients with severe congenital neutropenia who are on >8mcg/kg/day G-CSF therapy for a prolonged periods of time (23)(24)(25)(26).…”