A somatic MAP2K1 mutation in the HS component prompted selumetinib treatment, leading to a rapid response.<h4>Conclusion</h4>This case underscores the role of PAX5 in lineage plasticity and highlights the potential of targeted MEK inhibition in MAPK-driven HS arising from B-ALL.<h4>Trial registration</h4>The authors have confirmed clinical trial registration is not needed for this submission. The gene discussed is MAP2K1; the disease is acute lymphoblastic leukemia.