HAEM4:Juvenile Myelomonocytic Leukemia (JMML)

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

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).

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 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).

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

• 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

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EXAMPLE Book

1. 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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