Myeloid proliferations associated with Down syndrome

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:Transient Abnormal Myelopoiesis (TAM) Associated with Down Syndrome.

Other relevent pages include: HAEM4:Transient Abnormal Myelopoiesis (TAM) Associated with Down Syndrome, HAEM4:Myeloid Leukemia Associated with Down Syndrome

Note: author needs to merge content from Transient Abnormal Myelopoiesis (TAM) Associated with Down Syndrome AND Myeloid Leukemia Associated with Down Syndrome

(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)*

Linda D Cooley, MD, MBA, Children's Mercy Hospital, Kansas City, MO

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Myeloid neoplasms, secondary
Type	Myeloid neoplasms and proliferations associated with antecedent or predisposing conditions
Subtype(s)	Myeloid proliferations associated with Down syndrome

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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not applicable

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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)

Transient abnormal myelopoiesis is a preleukemic disorder that occurs only in neonates with constitutional trisomy 21. Transient abnormal myelopoiesis typically presents in the first week of life with leukocytosis, thrombocytopenia, hepatomegaly, and circulating megakaryoblasts, the latter of which contain an acquired GATA1 mutation. Although TAM can be fatal in 10% of patients, it most often resolves spontaneously, but is believed to persist in a “quiescent” state. By 5 years of age, 20% of patients progress to AMKL following an intervening remission and/or a preceding myelodysplastic-like syndrome. Down syndrome–AMKL has a favorable prognosis with enhanced chemotherapeutic responsiveness to cytarabine.

The disease evolution of TAM and DS-AMKL is currently conceived as a sequential multistep process of leukemogenesis. Trisomy 21 represents the critical “initiating” event. GATA1 mutation reflects a “secondary hit” to fetal liver hematopoiesis, particularly megakaryocytic-erythroid progenitors, that leads to TAM and confers some selective advantage.

Given the risk of progression to DS-AMKL, some advocate that all neonates with DS undergo routine screening for TAM with manual peripheral blood smear review and GATA1 mutation analysis. With detection of a GATA1 mutation, clinical assessment and routine laboratory screening is then suggested periodically throughout early childhood.

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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.

editv4:Genomic Gain/Loss/LOH

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not applicable

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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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Constitutional trisomy 21 or mosaic constitutional trisomy 21

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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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Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
GATA1	Most mutations insert a premature termination codon either by introducing a stop codon or frameshift. Mutations affecting the splice site at GATA1 exon 2 exon/intron boundary are next most frequent.	zinc finger DNA-binding transcription factor that plays a critical role in the normal development of hematopoietic cell lineages	N-terminally truncating somatic mutation	100%

Other Mutations

Not applicable

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Epigenomic Alterations

not applicable

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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In addition to trisomy 21, acquired GATA1 mutations are present in blast cells of TAM [1].

Somatic GATA1 mutations are pivotal in the development of TAM and have proven to be a marker of clonal identity in its evolution to DS-AMKL. The GATA1 gene is located on the X chromosome and encodes a zinc finger transcription factor that is essential for normal erythropoiesis and megakaryopoiesis. Its de novo protein product contributes to cytoplasmic maturation in megakaryocytes and organelle development in platelets, but functions as a negative regulator of megakaryocyte proliferation. Various acquired mutations in exon 2, or less commonly exon 3, ultimately yield a mutant N-terminally truncated GATA1 protein (designated GATA1s) that has been detected exclusively in patients with DS. GATA1 mutations (both single and multiple clones) have been detected in Guthrie card blood spots of patients with DS. 

In normal human development, the liver is the primary site of fetal (in utero) hematopoiesis. With birth, the hepatic microenvironment changes such that liver hematopoiesis is down-regulated while bone marrow simultaneously assumes this primary functionality. Given the clinical and laboratory manifestations of TAM, which include leukocytosis and circulating megakaryoblasts, often with hepatomegaly, TAM reflects perturbation of this normal developmental process. Transient abnormal myelopoiesis may arise in utero within the fetal liver with “spontaneous resolution” reflecting the natural process of hepatic hematopoietic down-regulation. 

TAM is the result of a multistep process in which trisomy 21 is the “initiating” event in disease pathogenesis. Trisomy 21 creates an environment, in utero, in which hematopoietic progenitor cells within fetal liver are primed for acquisition of either single or multiple somatic GATA1 mutations that reflect a “secondary hit,” thereby promoting hematopoietic dysregulation and emergence of TAM. With birth, hematopoiesis naturally transitions from fetal liver to bone marrow and the GATA1 megakaryoblastic clone becomes quiescent. However, this clone persists over time and undergoes other somatic mutations and epigenetic events ultimately lead to the impaired megakaryocytic differentiation and uncontrolled proliferation characteristic of DS-AMKL.

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Genetic Diagnostic Testing Methods

When TAM is suspected clinically, cytogenetic karyotypic analysis should be performed to establish constitutional trisomy 21, while GATA1 mutation analysis is also recommended to document clonality of the blast population. The presence of an acquired mutation(s) in exon 2 or exon 3 of the GATA1 gene on chromosome X establishes a diagnosis of TAM and serves as a potential marker for future disease monitoring in the development of AMKL. If a GATA1 mutation is detected in a neonate without clinical features of DS, cytogenetic analysis should still be performed to exclude DS mosaicism.

Familial Forms

not applicable

Additional Information

Also see HAEM4:Myeloid Proliferations Associated with Down Syndrome

Links

http://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2014-0304-CC?code=coap-site

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265448/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031718/pdf/11899_2016_Article_338.pdf

https://link.springer.com/content/pdf/10.1007%2Fs12185-016-1959-5.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551356/

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: “Myeloid proliferations associated with Down syndrome”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, https://ccga.io/index.php/HAEM5:Myeloid_proliferations_associated_with_Down_syndrome.