Genotype-phenotype correlation in cases of juvenile myelomonocytic leukemia with clonal RAS mutations
Abstrakt
In a recent issue of Blood, Matsuda et al reported 11 children with juvenile myelomonocytic leukemia (JMML) and clonal NRAS or KRAS mutations.1 Three patients showed improvement of various clinical and laboratory features over a 2- to 4-year period without chemotherapy or hematopoietic stem cell transplantation (HSCT). The authors correlate the comparatively mild course with a specific mutation predicting a glycine-to-serine substitution at position 12 in the NRAS or KRAS protein (G12S), and suggest that "no chemotherapy may be a recommended management" for JMML patients with NRAS/KRASG12S.
We have some reason to believe that these conclusions are premature. Available data do not support that RASG12S has weaker oncogenic activity than substitutions with valine, arginine, or aspartic acid.
Interestingly, the authors show that myeloid progenitor cells from their patients with G12S respond to granulocyte macrophage-colony stimulating factor (GM-CSF) in a comparable manner as other mutants (Figure 1B in Matsuda et al1 ). Others reported that HRASG12S led to focus induction in NIH3T3 cultures with a similar potency as substitutions with arginine or aspartic acid.2 We argue that the clinical course observed in the 3 children is not uncommon in JMML cases with similar hematologic features and age.
The European Working Group of Myelodysplastic Syndromes in Childhood (EWOG-MDS) has previously shown that platelet count 33 x 109/L or more and hemoglobin F less than 15% at diagnosis identifies a prognostically favorable subgroup in JMML with a 40% to 70% probability of survival at 2 to 4 years without HSCT.3 The relatively favorable course in the Matsuda patients is also because all 3 were less than 1 year old at diagnosis.4 It is known that infants with JMML without severe thrombocytopenia at diagnosis may experience transient improvement even without treatment