Abstracts
PO61
One Pathway, Divergent Hematopoiesis: NRAS and KRAS Mark Distinct Biological States in Juvenile Myelomonocytic Leukemia
Introduction/Background/Significance: Juvenile myelomonocytic leukemia (JMML) is defined by constitutive RAS/MAPK activation, yet convergence on a shared signaling pathway may obscure substantial allele-specific heterogeneity. NRAS- and KRAS-mutated JMML are frequently considered biologically equivalent, although their effects on hematopoietic organization and clinical behavior remain incompletely resolved. We examined whether RAS identity distinguishes discrete cellular, molecular, and outcome-related states within JMML.
Materials and Methods/Case Presentation/Objective: We retrospectively analyzed 34 children with somatic NRAS and/or KRAS alterations treated at a national hematology referral center. Somatic status was established using bone-marrow DNA and paired oral epithelial-cell DNA when available. Patients were classified as NRAS-only (n=20), KRAS-only (n=12), or dual NRAS/KRAS-mutated (n=2). Clinical characteristics, peripheral-blood composition, cooperating mutations, hematopoietic stem-cell transplantation, and overall survival were evaluated. Direct genotype comparisons were restricted to patients with mutually exclusive NRAS-only or KRAS-only disease.
Results/Description/Main Outcome Measure(s): KRAS-only JMML exhibited a higher peripheral-blood monocyte proportion than NRAS-only disease (27.2% vs 16.7%; P=0.023), despite identical median absolute monocyte counts (4.0 vs 4.0×10⁹/L; P=0.930). KRAS-only disease also showed a higher lymphocyte proportion (48.1% vs 39.0%; P=0.018). This separation between relative leukocyte composition and absolute monocytic burden indicated that RAS genotype was associated with the organization of circulating hematopoiesis rather than simply the magnitude of leukemic expansion. Non-RAS co-mutations were identified in 11 patients, most frequently involving PTPN11; both dual NRAS/KRAS-mutated cases also carried PTPN11 alterations, illustrating the complexity of pathway cooperation. Among 30 survival-evaluable patients, 15 died, but overall survival did not differ significantly between NRAS-only and KRAS-only disease. Eleven patients underwent transplantation.
Conclusion(s).: NRAS- and KRAS-mutated JMML represent biologically distinguishable RAS-driven states. Their contrasting leukocyte architectures, despite equivalent absolute monocytosis, reveal an allele-associated dimension of hematopoietic organization that is lost when RAS-mutated JMML is treated as a single entity. The absence of genotype-based survival separation further suggests that meaningful risk assessment will require integration of RAS identity with cooperating lesions, transplantation-related variables, and broader disease biology.
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References:
Materials and Methods/Case Presentation/Objective: We retrospectively analyzed 34 children with somatic NRAS and/or KRAS alterations treated at a national hematology referral center. Somatic status was established using bone-marrow DNA and paired oral epithelial-cell DNA when available. Patients were classified as NRAS-only (n=20), KRAS-only (n=12), or dual NRAS/KRAS-mutated (n=2). Clinical characteristics, peripheral-blood composition, cooperating mutations, hematopoietic stem-cell transplantation, and overall survival were evaluated. Direct genotype comparisons were restricted to patients with mutually exclusive NRAS-only or KRAS-only disease.
Results/Description/Main Outcome Measure(s): KRAS-only JMML exhibited a higher peripheral-blood monocyte proportion than NRAS-only disease (27.2% vs 16.7%; P=0.023), despite identical median absolute monocyte counts (4.0 vs 4.0×10⁹/L; P=0.930). KRAS-only disease also showed a higher lymphocyte proportion (48.1% vs 39.0%; P=0.018). This separation between relative leukocyte composition and absolute monocytic burden indicated that RAS genotype was associated with the organization of circulating hematopoiesis rather than simply the magnitude of leukemic expansion. Non-RAS co-mutations were identified in 11 patients, most frequently involving PTPN11; both dual NRAS/KRAS-mutated cases also carried PTPN11 alterations, illustrating the complexity of pathway cooperation. Among 30 survival-evaluable patients, 15 died, but overall survival did not differ significantly between NRAS-only and KRAS-only disease. Eleven patients underwent transplantation.
Conclusion(s).: NRAS- and KRAS-mutated JMML represent biologically distinguishable RAS-driven states. Their contrasting leukocyte architectures, despite equivalent absolute monocytosis, reveal an allele-associated dimension of hematopoietic organization that is lost when RAS-mutated JMML is treated as a single entity. The absence of genotype-based survival separation further suggests that meaningful risk assessment will require integration of RAS identity with cooperating lesions, transplantation-related variables, and broader disease biology.
Trademarked Items:
References:
