HAEM5:Acute erythroid 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:Pure Erythroid Leukemia.

Note: need to check if content remains the same

(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)*

Ashwini Yenamandra PhD FACMG

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Acute myeloid leukaemia
Type	Acute myeloid leukaemia, defined by differentiation
Subtype(s)	Acute erythroid leukaemia

Definition / Description of Disease

In the 2008 WHO classification, Acute Erythroid leukemia (AEL) was classified into two subtypes: Erythroleukemia (erythroid/myeloid) and Pure Erythroid Leukemia (PEL). However, in the 2016 WHO update, Erythroleukemia was merged into myelodysplastic syndrome, while PEL is now the only type of AEL. PEL is a distinct entity in the World Health Organization (WHO) classification system within the section of HAEM4:Acute Myeloid Leukemia (AML), Not Otherwise Specified. PEL is a rare form of acute leukemia with an aggressive clinical course and is characterized by an uncontrolled proliferation of immature erythroid precursors (proerythroblastic or undifferentiated).

Synonyms / Terminology

Also known as AML-M6b and Di Guglielmo syndrome due to the recognition of the work of Di Guglielmo.

Epidemiology / Prevalence

PEL is extremely rare with a small number of reported cases, accounting for 3-5% of AML cases. Median survival is usually three months.

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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PEL has an aggressive clinical course with neoplastic proliferation of immature erythroid precursor (proerythroblastic or undifferentiated) cells. Average survival rate is three months. PEL is characterized by neoplastic proliferation composed of >80% immature erythroid precursors of which proerythroblasts constitute ≥30%. Clinical features include profound anemia, circulating erythroblasts, pancytopenia, extensive bone marrow involvement, fatigue, infections, weight loss, fever, night sweats, hemoglobin level under 10.0 g/dL, and thrombocytopenia.

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Sites of Involvement

Bone marrow, Blood

Morphologic Features

PEL is characterized by medium to large erythroblasts with round nuclei, fine chromatin and one or more nucleoli (proerythroblast). Cytoplasm is deeply basophilic, often granular with demarcated vacuoles and are often Periodic-Acid-Schiff stain (PAS) positive. Blasts can be small and may resemble lymphoblasts. Cells are usually negative for Myeloperoxidase (MPO) and Sudan Black (SBB). Bone marrow biopsy may have undifferentiated cells.

Immunophenotype

Differentiated PEL may express Glycophorin and hemoglobin A, absence of myeloperoxidase (MPO) and other myeloid markers. Blasts are negative for HLA-Dr and CD34 but positive for CD117. Immature forms can be negative for Glycophorin or weekly expressed. Positive for Carbonic anhydrase 1, Gero antobody against the Gerbich blood group or CD36 especially at earlier stages of differentiation. CD41 and CD61 are negative.

Finding	Marker
Positive (universal)	Hemoglobin A, Glycophorin A, Spectrin, ABH blood group antigens, and HLA-DR
Positive (subset)	CD13, CD33, CD34, CD117 (KIT), and MPO, Gerbich blood group (Gero) antibody, carbonic anhydrase 1, and CD36, CD41 and CD61
Negative (universal)	Myeloid-associated markers such as MPO,CD13,CD33,CD61, B and T Cell markers -CD10, CD19, CD79a, CD2, CD3, CD5, monocytic markers CD11c CD14 Megakaryoblastic markers: CD61, Others: CD34, anti-kappa, anti-lambda, CD45
Negative (subset)	HLA-DR, CD34, Glycophorin A

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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The genetic abnormalities that have been identified in PEL are similar to that of AML and MDS and consists of complex chromosomal abnormalities including -5/del(5q), -7/del(7q), +8 and/or RUNX1 and TP53 mutations. Rearrangement of NFIA-CBFA2T3 with t(1;16)(p31;q24) and MYND8-RELA with t(11;20)(p11;q11) have been reported in rare cases. A complex karyotype with 46,XY,der(5)del(5)(p15.1p15.1)t(5;12;7)(p15.1;p13;q32),der(7)t(5;12;7),der(12)del(12)p13p13)t(5;12;7),del(13)(q12q14) was reported in a two year old boy with PEL.

Karyotype of two year old boy with PEL.

FISH for ETV6 and RUNX1 in two year old boy with PEL.

FISH for EGR1 and D5S23,D5S721 (5p-) in two year old boy with PEL.

FISH for RB1 and 13q34 (13q deletion) in two year old boy with PEL.

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
t(1;16)(p31;q24)	5’NFIA/ 3’CBFA2T3	der(16)	Rare
t(11;20)(p11;q11)	5’MYND8/ 3’RELA	der(11)	Rare

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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)

PEL has rapid and aggressive clinical course. Patients with PEL are treated similar to other types of AML. Stem cell transplantation (SCT) may have an improvement in the outcome of the disease. No therapeutic agents for specific target pathways are currently available.

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Individual Region Genomic Gain/Loss/LOH

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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

Chromosome Number	Gain/Loss/Amp/LOH	Region
5	Loss	Whole chromosome or q-arm
7	Loss	Whole chromosome or q-arm
8	Gain	Whole chromosome
17	Loss	P-arm

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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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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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JAK2, FLT3, RAS, NPM1, and CEBPA mutations have been reported to be rare in PEL. Intraclonal heterogeneity and founder mutations of TP53 were reported in 92% (11 out of 12 cases) while co-occurrence of TP53 mutation and deletion due to chromosome 17p abnormalities were detected in 73% of PEL cases.

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
EXAMPLE: TP53	EXAMPLE: R273H	EXAMPLE: Tumor Suppressor	EXAMPLE: LOF	EXAMPLE: 20%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	EXAMPLE: IDH1 R123H
Secondary Mutations	EXAMPLE: Trisomy 7
Mutually Exclusive	EXAMPLE: EGFR Amplification

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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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The molecular mechanism is not completely understood.

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Genetic Diagnostic Testing Methods

Morphology and IHC.

Familial Forms

Not Applicable

Additional Information

Differential Diagnosis: PEL without morphological differentiation of erythroid maturation can be difficult to distinguish from megakaryoblastic leukemia (AML), ALL or lymphoma. The erythroid precursor immunophenotype helps in the diagnosis. Some cases can be complex with concurrent erythroid megakaryocytic involvement.

Links

• Acute Erythroid Leukemia

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: “Acute erythroid leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/10/2025, https://ccga.io/index.php/HAEM5:Acute_erythroid_leukaemia.