not-yet-known not-yet-known not-yet-known unknown To the Editor: Juvenile myelomonocytic leukemia (JMML), characterized by splenomegaly, thrombocytopenia, peripheral blood monocytosis, elevated hemoglobin F, and hypersensitivity to granulocyte macrophage colony-stimulating factor (GM-CSF),1 is a clonal hematopoietic disorder of early childhood with constitutive activation of the Ras signaling pathway.2 JMML was previously classified as an overlap myeloproliferative/myelodysplastic neoplasm,3 and is under the myeloproliferative neoplasm (MPN) category in the updated 5th World Health Organization (WHO) classification of hematopoietic neoplasms.4 The clinical course and treatment of JMML are variable.5 6,7 Most JMML contain Ras pathway mutations including heterozygous somatic gain-of-function PTPN11, NRAS, and KRAS mutations in nonsyndromic children, and acquired biallelic inactivation of NF1 , CBL, or other tumor suppressor genes in children with neurofibromatosis type 1, CBL or other syndromes. Patients with germline mutations of the Ras signaling pathway (e.g. Noonan syndrome) may develop a transient myeloproliferative disorder in the first year of life. Therefore, it is critical to distinguish these syndromes from JMML by integrating clinical, pathological, and genetic features. Moreover, there are cases phenotypically resembling JMML but lacking a Ras pathway mutation and containing rare gene rearrangements of ALK , ROS1 , FIP1L1::RARA , FLT3 , NUP98 , and PDGFRB .8,9 These new genetic findings provide therapy targets (e.g. tyrosine kinase inhibitors), while creating diagnostic disputes because some of these translocations are considered acute myeloid leukemia (AML)-defining recurrent genetic aberrations or myeloid/Lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK).4,10 Here we report two unusual patients with JMML. Our first patient was a previously healthy 4-year-old female, who presented with 2 weeks of leg pain and fever. Peripheral blood count revealed WBC 85.8 k/mcL, Hgb 9.4 g/dL, and platelets 56 k/mcL. Peripheral blood flow cytometry showed approximately 16% monocytes and 15% blasts (CD45 dim+, CD34+, CD117+, CD33+, CD38+, CD13+, CD11c+, CD64 partial+, HLADR+, and CD4 dim+, MPO-). A bone marrow biopsy revealed hypercellularity with myeloid predominance and 11% myeloblasts (Figure 1A and B). A diagnosis of JMML (based on 4th WHO classification) was favored, given increased blasts, monocytosis, and negative FISH studies for BCR::ABL1 . Cytogenetics showed abnormal karyotypes with trisomy 6. Next-generation sequencing (NGS) identified NUP98::NSD1 fusion and KRAS G12D mutation (c.35G>A, 28.2% variant allele fraction (VAF)). The patient received chemotherapy (fludarabine, cytarabine, and azacitidine), with 5.7% minimal residual disease (MRD) by flow cytometry after three cycles of chemotherapy. Then the patient received a bone marrow transplant (BMT) with busulfan, cyclophosphamide, and melphalan conditioning regimen. Six cycles of azacitidine maintenance were started on day 165 post-BMT and the patient remains in complete remission two years after transplant. Our second patient was a 10-month-old male, who presented with poor weight gain, abdominal swelling, and upper respiratory infection. The peripheral blood smear showed monocytosis (20%) and rare blasts (1%). The bone marrow showed hypercellularity with approximately 7% blasts (CD34+, CD38+, CD7+, dim CD2+, and HLADR+ by flow cytometry) and no overt dysplasia (Figure 1C-F). NGS of the myeloid neoplasm panel identified PTPN11 p.Glu76Lys (48% VAF) in the bone marrow aspirate. FISH studies and cytogenetics were reported to be normal. The overall findings are consistent with JMML with PTPN11 mutation. The patient received 3 cycles of Azacytidine and Fludarabine (MRD negative at the end of chemotherapy), followed by BMT using busulfan, cyclophosphamide, and melphalan conditioning regimen. The patient was in remission for JMML and closely monitored after the transplant. Follow-up NGS was negative for PTPN11 mutation and the same mutation was absent in an oral mucosa sample.