HAEM5:Acute myeloid leukaemia with DEK::NUP214 fusion

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) with t(6;9)(p23;q34.1); DEK-NUP214.

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Primary Author(s)*

Jennelle C. Hodge, PhD, FACMG

Cancer Category / Type

Acute Myeloid Leukemia

Cancer Sub-Classification / Subtype

Acute myeloid leukemia (AML) with t(6;9)(p23;q34.1) resulting in DEK-NUP214 fusion

Definition / Description of Disease

This is a distinct entity in the World Health Organization (WHO) classification system, and the most common associated French-American-British (FAB) classifications are M2, M4 and M1.

Synonyms / Terminology

None

Epidemiology / Prevalence

Accounts for 0.7-1.8% of AML, occurring in both children (median age of 13 years) and adults (median age of 35-44 years).

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the table)

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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Usually presents with anemia and thrombocytopenia and often with pancytopenia. In adults, the median white blood cell count is 12x10^9/L, which is generally lower than other AML types.

Sites of Involvement

Bone marrow

Morphologic Features

This AML subtype may present with or without monocytic features and is frequently associated with basophilia (44-62% of cases) and multilineage dysplasia (most commonly granulocytic and erythroid, and less often megakaryocytic dysplasia). Auer rods occur in ~1/3 of cases and ringed sideroblasts may also occur. The peripheral blood or bone marrow have >20% blasts characterized by a non-specific myeloid immunophenotype.

Immunophenotype

The characteristic immunophenotype of the blasts associated with this entity is listed in the table below. In addition, basophils may present as separate clusters of CD123+, CD33+ CD38+ and HLA-DR- cells.

Finding	Marker
Positive (universal)	Myeloperoxidase (MPO), CD9, CD13, CD33, CD38 CD123, and HLA-DR
Positive (subset)	KIT(CD117), CD34, CD15, CD64 (monocyte-associated marker), and Dexoynucleotidyl Transferase (TdT)
Negative (universal)
Negative (subset)

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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This AML subtype is classified based on the presence of a t(6;9)(p23;q34.1), which results in fusion of the 5’ portion of DEK at “6p23” (specifically 6p22.3[hg38]) and the 3’ portion of NUP214(CAN) at “9q34.1” (specifically 9q34.13[hg38]). The breakpoints are intronic, producing an in-frame fusion. The DEK-NUP214 fusion present on the derivative chromosome 6 is considered the pathogenic entity as the reciprocal NUP214-DEK fusion on chromosome 9 does not appear to be transcribed. Typically the DEK-NUP214 fusion presents as the sole abnormality but can be part of a complex karyotype.

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
t(6;9)(p23;q34.1)	5'DEK / 3'NUP214(CAN)	der(6)	0.7-1.8% of AML

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)

This translocation has traditionally been associated with a poor prognosis in both adult and pediatric cases. Of note, a 2014 retrospective analysis suggests a better outcome for pediatric patients with this translocation than previously reported. Elevated white blood cell counts and higher bone marrow blast percentages are associated with shorter periods of overall survival and disease-free survival, respectively.

Limited data suggests early allogeneic stem cell transplantation may be associated with better overall survival compared to patients without transplantation, suggesting accurate diagnosis for these patients is crucial.

The concurrent presence of FLT3-ITD does not appear to negatively impact survival in the pediatric population.

Cases with the 6;9 translocation and <20% blasts are not currently classified as AML, which is controversial. Such cases should have close follow-up to monitor for development of more definitive evidence of AML or may be treated as AML if clinically appropriate.

Individual Region Genomic Gain / Loss / LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)

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).

editv4:Genomic Gain/Loss/LOH

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Not applicable

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: 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)

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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Not applicable

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 and common as well either disease defining and/or clinically significant. Can include references 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.)

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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COSMIC does not have specific information on mutations related to this subtype of AML.

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	FLT3-ITD (69% of children and 78% of adults)
Secondary Mutations
Mutually Exclusive	FLT3-TKD is very uncommon

Epigenomic Alterations

Not applicable

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in 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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The molecular mechanism is not completely understood, but the fusion protein is known to act as an aberrant transcription factor, alter nuclear transport and induce myeloid cell-specific global protein synthesis.

Genetic Diagnostic Testing Methods

Karyotype, FISH, RT-PCR

Familial Forms

Not applicable

Additional Information

Not applicable

Links

DEK

NUP214

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: “Acute myeloid leukaemia with DEK::NUP214 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_DEK::NUP214_fusion.