Correlation of Clinical Features With the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Juvenile Myelomonocytic Leukemia

Abstract

Mutations in RAS, neurofibromatosis type 1 (NF1), and PTPN11, constituents of the granulocyte-macrophage colonystimulating factor signaling pathway, have been recognized in patients with juvenile myelomonocytic leukemia (JMML). We assessed 71 children with JMML for NRAS, KRAS, and PTPN11 mutations and evaluated their clinical significance. Of the 71 patients, three had been clinically diagnosed with neurofibromatosis type 1, and PTPN11 and NRAS/KRAS mutations were found in 32 (45%) and 13 (18%) patients, respectively. No simultaneous aberrations were found. Compared with patients with RAS mutation or without any aberrations, patients with PTPN11 mutation were significantly older at diagnosis and had higher fetal Hb levels, both of which have been recognized as poor prognostic factors. As was expected, overall survival was lower for patients with the PTPN11 mutation than for those without (25 versus 64%; p ϭ 0.0029). In an analysis of 48 patients who received hematopoietic stem cell transplantation, PTPN11 mutations were also associated with poor prognosis for survival. Mutation in PTPN11 was the only unfavorable factor for relapse after hematopoietic stem cell transplantation (p ϭ 0.001). All patients who died after relapse had PTPN11 mutation. These results suggest that JMML with PTPN11 mutation might be a distinct subgroup with specific clinical characteristics and poor outcome.

RASA4undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

“…The association of PTPN11 mutation with RASA4 TSS2 methylation is compatible with the observation that PTPN11-mutant cases tend to run a more aggressive clinical course. 11,12 Conversely, there was only one patient with CBL alteration among 42 in the highest methylation tertile, but 8 CBL-mutant cases out of 42 in the lowest tertile (P = 0.04, chi-square test). A recent exome-wide sequencing study identified mutations in SETBP1 and JAK3 as genetic lesions in JMML with probable prognostic impact, but information on these mutations was unavailable in our cohort, precluding a comparison with RASA4 methylation.…”

“…[5][6][7][8][9] Although these mutations are thought to represent the cardinal genetic feature of JMML, it is still unclear if and how they determine treatment resistance. [10][11][12] Additional genetic changes frequently observed in JMML include chromosomal aberrations, most notably monosomy 7, which is detected in approximately 25% of cases. 1,13 We recently reported that the strongest prognostic factor on the molecular level is neither Ras pathway mutation nor karyotype but the presence of DNA hypermethylation at several target genes, 4 suggesting an important role of epigenetic events in the pathobiology of resistant JMML.…”

Childhood Myelodysplastic Syndrome: Focus on the Approach to Diagnosis and Treatment of Juvenile Myelomonocytic Leukemia

“…Such factors include older age at diagnosis (Ͼ2 years), increased fetal hemoglobin for age (Hgb F), and/or a platelet count under 33,000/uL at presentation, as well as female sex in some studies. 34 37 In their study, mutation of PTPN11 was associated with older age at diagnosis (Ͼ24 months), increased Hgb F (Ͼ10%), reduced overall survival, and, importantly, appeared to be an unfavorable prognostic factor predicting relapse following transplantation.…”

RAS diseases in children

“…In JMML, these somatic gain-of-function mutations occur in NRAS and KRAS and are found in leukemic cells at diagnosis in 20-25% of cases. 44,50,51,63 Rarely, insertions are noted. 64 For both, NRAS-and KRAS-associated disease, acquired loss…”

“…Mutations were often subclonal and were involved in the progression of leukemia.82 Genetic alterations in SRFS2, TET2, RUNX1, JAK2 and ASXL1 do not play a significant role in JMML. 51,75,[83][84][85][86] Similarly, inactivation of the TP53 tumor suppressor gene and internal tandem duplication and activation of the Fms-like tyrosine kinase 3 (FLT3) gene are generally absent in JMML. 87,88 With the paucity of genetic lesions, epigenetic changes such as abnormal DNA methylation pattern are of particular interest.…”