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).

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

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

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	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). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

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)

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

Please incorporate this section into the relevant tables found in:

• 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).

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Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: 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 references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

editv4:Characteristic Chromosomal Aberrations / Patterns

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

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Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, 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).

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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

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

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.

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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

editUnassigned References

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Familial Forms

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Additional Information

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Links

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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 Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

*Citation of this Page: “Juvenile myelomonocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, 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.