Abstracts
PO62
Molecular Subtype-Resolved Immune Architecture Defines Distinct Lymphocyte States in Juvenile Myelomonocytic Leukemia
Introduction/Background/Significance: Juvenile myelomonocytic leukemia (JMML) is characterized by aberrant RAS-pathway signaling, yet its biological heterogeneity may extend well beyond the malignant myeloid compartment. We investigated whether PTPN11-, NRAS-, and KRAS-mutated JMML are associated with distinct patterns of circulating lymphocyte organization and whether these immune phenotypes retain prognostic relevance after accounting for established clinical features.
Materials and Methods/Case Presentation/Objective: We analyzed 96 children with JMML. Molecular data were available for 89 patients, lymphocyte-subset phenotyping for 66, and survival data for 76. Primary analyses compared mutually exclusive PTPN11-only (n=29), NRAS-only (n=17), and KRAS-only (n=10) groups. Ten prespecified immune endpoints across 20 contrasts were evaluated using age- and sex-adjusted HC3 regression with false-discovery-rate correction. Survival associations were examined using univariable and clinically adjusted Cox models.
Results/Description/Main Outcome Measure(s): Five genotype-immune associations remained significant after multiplicity correction. Relative to PTPN11-only JMML, KRAS-only disease showed a higher complete-blood-count lymphocyte proportion (+21.05 percentage points; 95% CI, 11.59-30.51; adjusted P=0.000129) and a higher flow-reported lymphocyte proportion (+25.15 points; 95% CI, 7.45-42.84; adjusted P=0.0268). Conversely, NRAS-only disease showed lower CD3+ T-cell proportion (−15.47 points; adjusted P=0.038), lower CD4+ T-cell proportion (−14.55 points; adjusted P=0.000129), and a lower CD4 ratio (−1.06; adjusted P=0.00637). Absolute lymphocyte and monocyte counts were comparable across molecular groups, indicating reorganization of immune composition rather than generalized cellular expansion or depletion. Among 76 survival-evaluable patients, 42 died. A higher lymphocyte proportion was associated with lower mortality in univariable analysis (HR, 0.76 per 10-point increase; P=0.027), but this association attenuated after adjustment for age and platelet count (HR, 0.82; P=0.113).
Conclusion(s).: Molecular subtype delineates distinct circulating immune architectures in JMML. KRAS-only disease is associated with a lymphocyte-enriched configuration, whereas NRAS-only disease is characterized by relative T-cell and CD4+ depletion. These findings uncover immune organization as a previously underappreciated dimension of JMML heterogeneity and suggest that genotype-associated immune states may reflect broader differences in disease biology. Prospective single-cell and functional studies are warranted to define their cellular origins, biological significance, and potential therapeutic relevance.
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Materials and Methods/Case Presentation/Objective: We analyzed 96 children with JMML. Molecular data were available for 89 patients, lymphocyte-subset phenotyping for 66, and survival data for 76. Primary analyses compared mutually exclusive PTPN11-only (n=29), NRAS-only (n=17), and KRAS-only (n=10) groups. Ten prespecified immune endpoints across 20 contrasts were evaluated using age- and sex-adjusted HC3 regression with false-discovery-rate correction. Survival associations were examined using univariable and clinically adjusted Cox models.
Results/Description/Main Outcome Measure(s): Five genotype-immune associations remained significant after multiplicity correction. Relative to PTPN11-only JMML, KRAS-only disease showed a higher complete-blood-count lymphocyte proportion (+21.05 percentage points; 95% CI, 11.59-30.51; adjusted P=0.000129) and a higher flow-reported lymphocyte proportion (+25.15 points; 95% CI, 7.45-42.84; adjusted P=0.0268). Conversely, NRAS-only disease showed lower CD3+ T-cell proportion (−15.47 points; adjusted P=0.038), lower CD4+ T-cell proportion (−14.55 points; adjusted P=0.000129), and a lower CD4 ratio (−1.06; adjusted P=0.00637). Absolute lymphocyte and monocyte counts were comparable across molecular groups, indicating reorganization of immune composition rather than generalized cellular expansion or depletion. Among 76 survival-evaluable patients, 42 died. A higher lymphocyte proportion was associated with lower mortality in univariable analysis (HR, 0.76 per 10-point increase; P=0.027), but this association attenuated after adjustment for age and platelet count (HR, 0.82; P=0.113).
Conclusion(s).: Molecular subtype delineates distinct circulating immune architectures in JMML. KRAS-only disease is associated with a lymphocyte-enriched configuration, whereas NRAS-only disease is characterized by relative T-cell and CD4+ depletion. These findings uncover immune organization as a previously underappreciated dimension of JMML heterogeneity and suggest that genotype-associated immune states may reflect broader differences in disease biology. Prospective single-cell and functional studies are warranted to define their cellular origins, biological significance, and potential therapeutic relevance.
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References:
