CSF3R T618I mutant chronic myelomonocytic leukemia (CMML) defines a proliferative CMML subtype enriched in ASXL1 mutations with adverse outcomes

CSF3R T618I mutated chronic myelomonocytic leukemia: A proliferative subtype with a distinct mutational profile

“…Although the mechanism by which the CSF3R mutation contributes to pathogenesis in CMML is largely unknown, it seems that the CSF3R T618I mutation, a membrane-proximal mutation, results in ligand-independent receptor activation and constitutive downstream signaling through JAK2, whereas the other membrane-distal CSF3R mutations may lead to ligand hypersensitivity and increased cell surface CSF3R expression [ 6 , 18 ]. This proposed mechanism may explain why leukocytosis (proliferative subtype) is commonly associated with CSF3R T618I mutated CMML (a higher median WBC of 38 × 10 9 /L in 6 cases [16] and WBC of 35 × 10 9 /L in our case), whereas the non-proliferative subtype is commonly associated with CSF3R non-T618I mutated CMML (a median WBC of 11.3 × 10 9 /L in 6 cases [15] ).…”

“…Notably, the CSF3R mutation is rare in CMML, with only ∼40 cases being reported (∼30 cases with CSF3R non-T618I and ∼10 cases with CSF3R T618I, accounting for ∼4% and ∼1% of CMML, respectively) [ 4 , 8 , [15] , [16] , [17] ]; our case is thus unusual. Although the mechanism by which the CSF3R mutation contributes to pathogenesis in CMML is largely unknown, it seems that the CSF3R T618I mutation, a membrane-proximal mutation, results in ligand-independent receptor activation and constitutive downstream signaling through JAK2, whereas the other membrane-distal CSF3R mutations may lead to ligand hypersensitivity and increased cell surface CSF3R expression [ 6 , 18 ].…”

“…CMML is characterized by recurrent mutations in TET2 (∼60%), ASXL1 (∼40%), SRSF2 (∼50%), SETBP1 (∼15%), and genes in the RAS signaling pathway (∼30%) [ 1 , 2 ], characteristic of an aging-associated disease with mutations affecting epigenetic (DNA methylation and histone modification), splicing, and signaling pathways. Compared to CSF3R unmutated CMML, CSF3R T618I mutated CMML (including our case) seems to have more frequent mutations in ASXL1 (∼80%) and infrequent mutations in TET2 (0/8, 0%) or SRSF2 (1/8, ∼14%), a feature suggestive of minimal disturbance of DNA methylation and splicing pathways [ 16 , 17 ]. This contrasts with the mutational profile in CSF3R non-T618I mutated CMML, with the frequency of TET2 and SRSF2 mutations (∼30% for each) similar to CSF3R unmutated CMML [ 4 , 8 , 15 ].…”

CSF3R T618I mutant myelodysplastic/myeloproliferative neoplasm in the elderly: An age-related disease with unfavorable prognosis

“…CMML with CSF3R T618I mutation was extremely rare with only six reported cases [11] . Its estimated frequency in CMML patients was 0.62%.…”

“…Its estimated frequency in CMML patients was 0.62%. These cases were characterized by a frequent association with ASXL1 mutation and proliferative disease, younger age, and an unfavorable prognosis [11] . Patient 2 exhibited similar features except for an old age.…”