Juvenile myelomonocytic leukemia in the molecular era: a clinician’s guide to diagnosis, risk stratification, and treatment

Abstract

Juvenile myelomonocytic leukemia is an overlapping myeloproliferative and myelodysplastic disorder of early childhood. It is associated with a spectrum of diverse outcomes ranging from spontaneous resolution in rare patients to transformation to acute myeloid leukemia in others that is generally fatal. This unpredictable clinical course, along with initially descriptive diagnostic criteria, led to decades of productive international research. Next generation sequencing now permits more accurate molecular diagnoses in nearly all patients. However, curative treatment is still reliant on allogeneic hematopoietic cell transplantation for most patients, and additional advances will be required to improve risk stratification algorithms that distinguish those that can be observed expectantly from others who require swift hematopoietic cell transplantation.

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

“…Canonical RAS pathway mutations in the PTPN11, NRAS, KRAS, NF1, CBL, and rarely RRAS genes are present in leukemic cells of more than 95% of patients and define genetically and clinically distinct subtypes. 135,136 Two subtypes are defined by germline events in either NF1 or CBL, which progress to malignancy with acquired biallelic inactivation of the respective genes in hematopoietic cells. The other subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous, somatic gain-of-function mutations in children without germline disease.…”

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…JMML, which accounts for 1% of pediatric leukemias, has a median age of onset of 2 years [ 189 , 204 , 205 , 224 , 225 ]. Over 90% of JMML driver mutations involve five genes in the canonical RAS pathway ( PTPN11, NRAS, KRAS, NF1 , CBL) , with approximately 35% being somatic PTPN11 (gain of SHP-2 function) exon 3 or 13 mutations [ 133 , 189 , 190 , 204 , 205 , 224 , 225 , 226 , 227 , 228 , 229 ].…”

“…Over 90% of JMML driver mutations involve five genes in the canonical RAS pathway ( PTPN11, NRAS, KRAS, NF1 , CBL) , with approximately 35% being somatic PTPN11 (gain of SHP-2 function) exon 3 or 13 mutations [ 133 , 189 , 190 , 204 , 205 , 224 , 225 , 226 , 227 , 228 , 229 ]. Hypersensitivity of JMML progenitors to GM-CSF, IL3 and TNFa in vitro, hyperproliferation of monocytic and/or granulocytic lineages in vivo, thrombocytopenia, and increased fetal hemoglobin (HbF in 50–60% of patients) are common JMML features, with occasional transformation to ALL, suggesting a disease of, or expressed in, multipotent HSC/MPP [ 204 , 205 , 224 , 225 , 226 , 227 , 228 , 229 ]. A number of recent studies have investigated the cellular origin and clonal evolution of JMML using iPS cell [ 230 , 231 , 232 , 233 , 234 , 235 , 236 ] and xenograft models [ 237 , 238 , 239 ].…”

Juvenile Myelomonocytic Leukemia in a Child: A Case Report of Palliative Chemotherapy and Literature Review Applied to Limited Resources Centers

“…JMML is associated with two inherited diseases: neurofibromatosis type 1 (NF-1) and Casitas B-lineage (CBL)-syndrome [ 1 ]. There are five subtypes of JMML: PTPN11-mutated JMML, NRAS-mutated JMML, KRAS-mutated JMML, NF-1-mutated JMML, and CBL-mutated JMML [ 4 ]. Cytogenetic analysis of JMML patients showed monosomy 7 in 24–33% of patients, other chromosomal abnormalities in 10–27%, and normal karyotype in 40–60% [ 5 ].…”