HAEM5:Juvenile myelomonocytic leukaemia

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4: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

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Myeloproliferative neoplasms
Type	Myeloproliferative neoplasms
Subtype(s)	Juvenile myelomonocytic leukaemia

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

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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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)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Chromosomal Rearrangements (Gene Fusions)

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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)

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

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).

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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Prevalence	Karyotype
25%	Monosomy 7
10%	Other abnormalities
65%	Normal karyotype

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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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).

Epigenomic Alterations

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

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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Molecular driver mutations within the RAS signaling pathway genes PTPN11, NRAS, KRAS, NF1, and CBL are identified in 85-90% of patients with JMML.

Genetic Diagnostic Testing Methods

• 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

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Familial Forms

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Additional Information

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References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

*Citation of this Page: “Juvenile myelomonocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Juvenile_myelomonocytic_leukaemia.

Other Sections

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.