HAEM4Backup:Juvenile Myelomonocytic Leukemia (JMML)
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Primary Author(s)*
Sarah Rapisardo, PhD, FACMG | Assistant Professor, Pathology
Associate Director | Division of Molecular Pathology, Genetics and Genomics
Duke University Health System Clinical Laboratories
Cancer Category/Type
Myeloproliferative neoplasm
Cancer Sub-Classification / Subtype
Juvenile myelomonocytic leukemia (JMML)
Definition / Description of Disease
JMML is a clonal hematopoietic disorder of childhood characterized by proliferation of the granulocytic and monocytic lineages.
Synonyms / Terminology
Juvenile chronic myelomonocytic leukemia
Epidemiology / Prevalence
JMML is a rare disease, with an annual incidence of approximately 0.13 cases per 100,000 children 0-14 years of age (WHO: Baumann I et al). Patient age at diagnosis ranges from 1 month to early adolescence, with a median age at presentation of 2 years (WHO: Baumann I et al, Caywood and Kolb, UpToDate). There is a male predominance, with boys affected nearly twice as frequently as girls.
Clinical Features
Children with JMML typically present with symptoms related to infiltration of the bone marrow and other organs. Approximately one half of all patients have lymphadenopathy (WHO), and one-third of children will have an acute presentation with fever, signs of upper respiratory infection, organomegaly, and cutaneous findings (Caywood and Kolb, UpToDate).
Sites of Involvement
Peripheral blood and bone marrow. In nearly all cases, leukemic infiltration of the liver and spleen is found; any tissue can be infiltrated, most commonly the lymph nodes, skin, respiratory system and gut. (WHO: Baumann I et al).
Morphologic Features
A peripheral blood smear is the most important specimen for diagnosis and typically shows leukocytosis, thrombocytopenia, and anemia (WHO: Baumann I et al). Bone marrow findings typically include hypercellularity with granulocytic proliferation, with <20% blasts and minimal dysplasia (WHO: Baumann I et al).
Immunophenotype
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| Finding | Marker |
|---|---|
| Positive (universal) | EXAMPLE CD1 |
| Positive (subset) | EXAMPLE CD2 |
| Negative (universal) | EXAMPLE CD3 |
| Negative (subset) | EXAMPLE CD4 |
Chromosomal Rearrangements (Gene Fusions)
Chromosomal translocations resulting in fusion genes have been only rarely reported in JMML patients with monosomy 7 (without mutations in the canonical RAS pathway)[1].
Importantly, exclusion of KMT2A rearrangements and the absence of BCR::ABL1 are diagnostic criteria for JMML. (PMID: Arber ICC PMID: 35767897 and Khoury WHO PMID: 35732831)
Characteristic Chromosomal Aberrations / Patterns
| Prevalence | Karyotype |
| 25% | Monosomy 7 |
| 10% | Other abnormalities |
| 65% | Normal karyotype |
Genomic Gain/Loss/LOH
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| Chromosome Number | Gain/Loss/Amp/LOH | Region |
|---|---|---|
| EXAMPLE 8 | EXAMPLE Gain | EXAMPLE chr8:0-1000000 |
| EXAMPLE 7 | EXAMPLE Loss | EXAMPLE chr7:0-1000000 |
Gene Mutations (SNV/INDEL)
Frequent gene mutations[2] are summarized below:
| Gene | Mutation | Oncogene/Tumor Suppressor/Other | Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) | Prevalence (COSMIC/TCGA/Other) |
|---|---|---|---|---|
| PTPN11 | Multiple | Oncogene | Somatic GOF | 40% |
| KRAS, NRAS | G12, G13, Q61 | Oncogene | Somatic GOF | 15-20% |
| NF1 | Multiple | Tumor Suppressor | Germline mutation with acquired biallelic inactivation in hematopoietic cells | 10-15% |
| CBL | Multiple | Tumor Suppressor | Germline mutation with acquired biallelic inactivation in hematopoietic cells | 10-15% |
Other Mutations
Secondary molecular abnormalities have been reported in JMML.
| Type | Gene/Region/Other |
|---|---|
| Other Mutated Genes Identified by Exome Sequencing | ASXL1, DNMT3A, EZH2, GATA2, RRAS, RRAS2, RUNX1, SETBP1, SH2B3, ZRSR2 (Stieglitz E et al, PMID 26457647) |
| Mutually Exclusive | Although driver mutations in NRAS, KRAS, PTPN11, CBL1, and NF1 typically thought to be mutually exclusive, coexisting mutations were identified in 11% of patients (Stieglitz E et al, PMID 26457647). |
Epigenomics (Methylation)
Mutations in epigenetic modifiers genes including ASXL1, EZH2, and DNMT3A are observed in a subset of JMML (identified 14% of patients).[3]
Genes and Main Pathways Involved
Molecular driver mutations within the RAS signaling pathway genes PTPN11, NRAS, KRAS, NF1, and CBL are identified in 85-90% of patients with JMML.
Diagnostic Testing Method[4]
- Clinical and hematologic features:
- Peripheral blood monocyte count > 1 x 109/L (present in most cases)
- Splenomegaly (present in >95 % cases at presentation)
- Blast percentage in peripheral blood and bone marrow < 20%
- Absence of BCR::ABL1
- Genetic studies (one finding required):
- Somatic mutation in PTPN11, KRAS, NRAS, or RRAS
- Germline NF1 mutation and loss of heterozygosity of NF1 or clinical diagnosis of neurofibromatosis type 1
- Germline CBL mutation and loss of heterozygosity of CBL
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
The progression of JMML is variable. While some studies identify a prognostic difference based on the molecular driver mutation, with PTPN11, KRAS, and NRAS mutations showing a more aggressive disease course (WHO: Baumann I et al), another report identified the number of mutations present at diagnosis (rather than the type of mutations), as a prognostic factor, with patients harboring two or more somatic alterations at diagnosis having worst event-free and overall survival rates than those with one or no mutations (Stieglitz E et al, PMID 26457647). Spontaneous regression of JMML is observed in most children with CBL mutations. The only curative treatment is allogeneic stem cell transplant, with a 5-year event free survival of approximately 44-53% (Meynier S and Rieux-Laucat, PMID 31980238).
Genetic Susceptibility
Approximately 25% of patients with JMML have inherited syndromes that predispose to the development of JMML (Stieglitz E et al, PMID 26457647). Specifically, the RASopathies are a class of autosomal dominant developmental disorders caused by germline mutations in the Ras/MAPK signaling pathway, with clinical features that include facial dysmorphism; cardiac defects; cutaneous, musculoskeletal, and ocular abnormalities; reduced growth; neurocognitive deficits; and increase cancer risk (including JMML) (Rauen KA, PMID 23875798). Increased risk of JMML is reported in the following RASopathies:
1. Neurofibromatosis type I (OMIM # 162200) with germline mutations in the NF1 gene.
2. Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (OMIM #613563) with germline mutations in the CBL gene.
3. Noonan syndrome (OMIM # 163950) with germline mutations in PTPN11.
Other Information
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Links
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References
- ↑ Meynier, Sonia; et al. (2020-09). "After 95 years, it's time to eRASe JMML". Blood Reviews. 43: 100652. doi:10.1016/j.blre.2020.100652. ISSN 1532-1681. PMID 31980238. Check date values in:
|date=(help) - ↑ Niemeyer, Charlotte M. (2018-11-30). "JMML genomics and decisions". Hematology. American Society of Hematology. Education Program. 2018 (1): 307–312. doi:10.1182/asheducation-2018.1.307. ISSN 1520-4383. PMC 6245977. PMID 30504325.
- ↑ Stieglitz, Elliot; et al. (2015-11). "The genomic landscape of juvenile myelomonocytic leukemia". Nature Genetics. 47 (11): 1326–1333. doi:10.1038/ng.3400. ISSN 1546-1718. PMC 4626387. PMID 26457647. Check date values in:
|date=(help) - ↑ Arber, Daniel A.; et al. (2022-09-15). "International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data". Blood. 140 (11): 1200–1228. doi:10.1182/blood.2022015850. ISSN 1528-0020. PMC 9479031 Check
|pmc=value (help). PMID 35767897 Check|pmid=value (help).
(use "Cite" icon at top of page)
EXAMPLE Book
- Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
Notes
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