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Abstract

Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder of early childhood with excessive proliferation of the myeloid and monocytic lineage. Deregulation of the RAS signal transduction pathway is thought to play a key role in its pathogenesis. We examined peripheral blood or bone marrow cells of 36 children with JMML for activating point mutations in codons 12, 13 and 61 of the NRAS and KRAS proto-oncogenes by allele-specific restriction assay, single-strand conformation polymorphism and/or direct sequencing. Codons 12, 13 and 61 of HRAS were examined in 26 of these patients. We detected RAS mutations in six cases (17%) located at N12 (n = 2), N13 (n = 3) and K13 (n = 1). In addition, we performed clonality studies on different cell lineages in four of these patients applying the RAS mutation, the karyotype and X-chromosome inactivation patterns as clonal markers. Erythroid cells carried mutant RAS, indicating clonal origin. In EBV B cell lines, one of three patients studied harbored a RAS mutation, while the other two patients had polyclonal B cells with wild-type RAS. T lymphocytes were examined in one patient; they were polyclonal and had wild-type RAS. It is likely that JMML is a heterogeneous disease with respect to clonal involvement of different lineages.

Chronic Myelomonocytic Leukemia and Atypical Chronic Myeloid Leukemia: Novel Pathogenetic Lesions

“…However, CMML patients are rarely found to have mutations in PTPN11 , 10 which is seen in significant proportion of patients with JMML. 11 In contrast, mutations in CBL -B, 12,13 RAS , 14-16 and ASXL1 17,18 are shared by CMML and JMML.…”

RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

“…Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder (MPD) of early childhood that originates from the multipotent hematopoietic stem and progenitor cell (HSPC) compartment. JMML is characterized by overproduction of mature and immature myeloid cells, including the erythroid lineage 1 . Without adequate treatment, survival for most children is < 1 year.…”

Validation of flow cytometric phospho-STAT5 as a diagnostic tool for juvenile myelomonocytic leukemia

“…3 GM-CSF binds to the alpha and beta subunits of its cell surface receptor, triggering two distinct signaling pathways: the Ras-MAPK (mitogen-activated protein kinase) pathway and the JAK-STAT (Janus-activated kinase–signal transducer and activator of transcription factor) pathway. In patients with JMML, Ras-MAPK signaling is constitutively activated by a spectrum of usually mutually exclusive mutations affecting genes, such as NRAS , KRAS , 4, 5 NF1 , 6 PTPN11 7 and CBL . 8, 9 …”