Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia

Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm of early childhood. Most of JMML patients experience an aggressive clinical course of the disease and require hematopoietic stem cell transplantation, which is currently the only curative treatment. JMML is characterized by RAS signaling hyperactivation, which is mainly driven by mutations in one of five genes of the RAS pathway, including PTPN11, KRAS, NRAS, NF1, and CBL. These driving mutations define different disease subtypes with specific clinico-biological features. Secondary mutations affecting other genes inside and outside the RAS pathway contribute to JMML pathogenesis and are associated with a poorer prognosis. In addition to these genetic alterations, JMML commonly presents aberrant epigenetic profiles that strongly correlate with the clinical outcome of the patients. This observation led to the recent publication of an international JMML stratification consensus, which defines three JMML clinical groups based on DNA methylation status. Although the characterization of the genomic and epigenomic landscapes in JMML has significantly contributed to better understand the molecular mechanisms driving the disease, our knowledge on JMML origin, cell identity, and intratumor and interpatient heterogeneity is still scarce. The application of new single-cell sequencing technologies will be critical to address these questions in the future.

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

“…In other myeloid malignancies, mutations in SWI/SNF genes seem to be extremely rare (< 1%), and, if present, they mostly affect ARID1A . This is the case for AML [ 51 ], CML [ 203 ], and myeloproliferative neoplasms such as juvenile myelomonocytic leukemia [ 204 , 205 ], chronic myelomonocytic leukemia [ 206 ], chronic neutrophilic leukemia [ 207 ], chronic eosinophilic leukemia [ 208 ], and others [ 112 , 209 – 213 ]. However, there are notable exceptions.…”

The Clinical Landscape of NRAS-mutated Juvenile Myelomonocytic Leukemia-like Myeloproliferation Includes Children With Costello Syndrome

“…Certain mutations in RAS pathway genes increase their activity, conferring a gain of function. NRAS and KRAS mutations cluster in the G12, G13, and Q61 residues, locking RAS in an active, GTP-bound state 4,5 . NF1 and CBL are tumor suppressing genes in which germline mutations occur in the context of neurofibromatosis type 1 and CBL syndrome, respectively, leading to enhanced RAS signaling 6…”

“…7 Hypermethylation has been associated with poor clinical outcome in JMML. 5 Approximately 7% of patients with JMML have been reported to have mutations in SH2B3, 7 a gene which encodes the tumor suppressor LNK that negatively regulates JAK/STAT signaling. Previous studies have demonstrated that patients with JMML have increased STAT5 phosphorylation.…”

“…In addition to ASXL1 , epigenetic modifiers have been demonstrated to be mutated in up to 15% of patients with JMML 7. Hypermethylation has been associated with poor clinical outcome in JMML 5…”

“…NRAS and KRAS mutations cluster in the G12, G13, and Q61 residues, locking RAS in an active, GTP-bound state. 4,5 NF1 and CBL are tumor suppressing genes in which germline mutations occur in the context of neurofibromatosis type 1 and CBL syndrome, respectively, leading to enhanced RAS signaling. 6 The majority of patients with JMML have a normal karyotype; however, up to 25% of patients have been described to have monosomy 7.…”