Acute myeloid leukaemia with CEBPA mutation
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) with Biallelic Mutations of CEBPA.
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Primary Author(s)*
Paul Defazio, MSc, Monash Health
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | Myeloid proliferations and neoplasms |
| Family | Acute myeloid leukaemia |
| Type | Acute myeloid leukaemia with defining genetic abnormalities |
| Subtype(s) | Acute myeloid leukaemia with CEBPA mutation |
Definition / Description of Disease
AML with biallelic CEBPA (CCAT/Enhancer Binding Protein Alpha) mutations is a distinct disease entity in the 2016 World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia[1].
Mutations in CEBPA have been divided into two types[2]. Firstly, frameshift mutations in the N-terminal region trans-activating domain (TAD) between the alternative translation initiation sites can abolish expression of the larger isoform by introducing premature stop codons; this results in overexpression of the shorter isoform, which appears to have a dominant negative effect on the larger CEPBA protein. Secondly, in-frame C-terminal mutations in the bZIP domain reduce the DNA-binding potential of CEBPA and its ability to dimerise with other CEBP family members. Most CEBPA-mutated AMLs exhibit more than one mutation[2]. Compound heterozygous mutations affecting both the N-terminal and C-terminal regions of the CEBPA protein are associated with favorable clinical outcome in the context of AML, in the absence of complex karyotype or FLT3 internal tandem duplications. Only biallelic CEBPA mutations are prognostically significant; monoallelic mutations do not have prognostic implications[3].
Synonyms / Terminology
None
Epidemiology / Prevalence
Approximately 6-15% of de novo AML and 15-18% of AML with normal karyotypes have monoallelic or biallelic CEBPA mutations[1][4]. There does not appear to be age or gender differences between CEBPA mutated and non-mutated AML. Inherited heterozygous CEBPA mutations have also been linked to familial AML[5]. Inherited CEBPA are associated with earlier-onset AML. Taskesen et al. reported that five of 71 (7%) CEBPA-mutant AML patients carried germline mutations[4].
Clinical Features
Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete 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 FeaturesThe content below was from the old template. Please incorporate above.AML with mutated CEBPA tends to have higher haemoglobin levels, lower platelet counts, lower lactate dehydrogenase levels and higher PB blast cell counts compared to CEBPA non-mutated AML[1]. There is also a lower frequency of lymphadenopathy and myeloid sarcoma in CEBPA mutated AML than in non-mutated AML[1].
Sites of Involvement
Blood, bone marrow
Morphologic Features
There are no distinctive morphological features of AML with CEBPA mutations. The vast majority of cases have features of AML with maturation or AML without maturation. Cases with monocytic or myelomonocytic features are less common.
Immunophenotype
Like in CEBPA wild-type AML, leukemic blasts usually express one or more of the myeloid-associated antigens CD13, CD33, CD65, CD11b, and CD15. HLA-DR and CD34 are also usually expressed on the majority of blasts. CD7, CD15, CD34, and HLA-DR expression are found in significantly more patients with biallelic CEBPA mutations than in unmutated patients[6]. Monocytic markers such as CD14 and CD64 are usually not expressed in AML with biallelic CEBPA mutations. Expression of CD56 and other lymphoid antigens is also uncommon.
| 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)The content below was from the old template. Please incorporate above.None
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: 3'ABL1 / 5'BCR EXAMPLE: der(22) EXAMPLE: 5% EXAMPLE: t(8;21)(q22;q22) EXAMPLE: 5'RUNX1 / 3'RUNXT1 EXAMPLE: der(8) EXAMPLE: 5%
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)
Patients with biallelic CEBPA mutations and a normal karyotype have a more favorable prognosis than those with monoallelic or no CEBPA mutations, with higher complete remission rates and longer disease-free survival, relapse-free survival, event-free survival, and overall survival[1]. Patients with abnormal karyotypes (but not complex karyotypes) and biallelic CEBPA mutations also have longer disease-free survival, event-free survival, and overall survival when compared to patients with monoallelic or no CEBPA mutations[1].
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. Do not delete table.)
| 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/LOHThe content below was from the old template. Please incorporate above.None
Chromosome Number Gain/Loss/Amp/LOH Region EXAMPLE: 8 EXAMPLE: Gain EXAMPLE: chr8:0-1000000 EXAMPLE: 7 EXAMPLE: Loss EXAMPLE: chr7:0-1000000
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. Do not delete table.)
| 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 / PatternsThe content below was from the old template. Please incorporate above.None
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 as 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. Do not delete table.)
| 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)The content below was from the old template. Please incorporate above.Pathogenic mutations in CEBPA are predominantly insertion/deletion frameshift mutations in the N-terminal TAD region and in-frame C-terminal bZIP mutations. No particular mutational hotspots exist but the following table records the most reported mutations in the COSMIC database (frequency based on a count out of 1523 mutations):
Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other) CEBPA c.939_940insAAG, p.K313_V314insK Oncogene LOF 52 CEBPA c.68_69insC, p.H24fs*84 Oncogene LOF 43 CEBPA c.247delC, p.Q83fs*77 Oncogene LOF 32 CEBPA c.936_937insCAG, p.Q312_K313insQ Oncogene LOF 28 CEBPA c.912_913insTTG, p.K304_Q305insL Oncogene LOF 24 Other Mutations
Concurrent mutations in NPM1 and FLT3 are seen less frequently in individuals with biallelic CEBPA mutations than in those with no or monoallelic mutations[4]. Conversely, mutations in GATA2 appear to occur more often in CEBPA single- and double-mutants[7]. The prognostic significance of these concomitant mutations is, however, unclear. Biallelic CEBPA mutations appear to confer a positive prognostic effect regardless of concomitant mutations.
Type Gene/Region/Other Concomitant Mutations NPM1, FLT3, GATA2 Secondary Mutations None Mutually Exclusive None
Epigenomic Alterations
None
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 InvolvedThe content below was from the old template. Please incorporate above.CEBPA, located on chromosome 19 band q13.1, encodes a transcription factor of the basic region leucine zipper (bZIP) family. It is involved in the coordination of myeloid differentiation and cellular growth arrest. Alternative translation initiation sites result in protein isoforms of different lengths.
CEPBA works in a tissue-specific manner to direct cellular differentiation by activating lineage-specific gene promoters. Interactions with the basal transcriptional apparatus (TBP/TFIIB), histone acetylators (CBP/p300), and chromatin-remodelling complexes (SWI/SNF) have all been implicated in lineage-specific gene activation by CEBPA. In the haematopoietic system there appears to be interplay between CEBPA and GATA factors[8]. CEBPA knockout mice show a complete lack of granulocytes while blasts accumulate in the bone marrow, suggesting an early block of myeloid maturation[9]. In the context of haematopoietic differentiation, evidence suggests CEBPA plays a role in regulating the expression of genes encoding growth factor receptors (e.g. granulocyte colony-stimulating factor) and secondary granule proteins (e.g. lactoferrin)[10][11]. It has also been implicated, along with NFI-A, in mediating miR-223 expression[12]. Studies indicate that CEBPA is not required for differentiation of granulocytes beyond the granulocyte-monocyte progenitor (GMP) stage, and that CEBPA controls stem-cell renewal with expression of Bmi-1 elevated in 'CEBPA knockouts[13]. Proliferation arrest also appears to be an important aspect of CEBPA function via interaction with CDK2/CDK4, upregulation of the p21 (WAF-1/CIP-1/SDI-1) protein and the SWI/SNF complex, and inhibition of the E2F complex[14][15][16][17][18]. This E2F inhibition leads to c-myc downregulation, which is required for granulocytic regulation[19]. Mutations in the C-terminal region of CEBPA abrogate CEBPA-E2F complex function[20]. The precise mechanism by which CEBPA mutants inhibit granulocytic differentiation in the context of AML is still unclear.
Genetic Diagnostic Testing Methods
Sanger sequencing, Next Generation Sequencing
Familial Forms
Familial mutations of CEBPA have been described in several families[5][21][22]. Typically, these are N-terminal mutations that are later joined by a somatic C-terminal mutation on the opposite allele leading to AML.
Additional Information
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Links
References
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- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p142-144.
- ↑ 2.0 2.1 Pabst, T.; et al. (2007). "Transcriptional dysregulation during myeloid transformation in AML". Oncogene. 26 (47): 6829–6837. doi:10.1038/sj.onc.1210765. ISSN 0950-9232. PMID 17934489.
- ↑ Wouters, Bas J.; et al. (2009). "Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome". Blood. 113 (13): 3088–3091. doi:10.1182/blood-2008-09-179895. ISSN 1528-0020. PMC 2662648. PMID 19171880.
- ↑ 4.0 4.1 4.2 Taskesen, Erdogan; et al. (2011). "Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity". Blood. 117 (8): 2469–2475. doi:10.1182/blood-2010-09-307280. ISSN 1528-0020. PMID 21177436.
- ↑ 5.0 5.1 Smith, Matthew L.; et al. (2004). "Mutation of CEBPA in familial acute myeloid leukemia". The New England Journal of Medicine. 351 (23): 2403–2407. doi:10.1056/NEJMoa041331. ISSN 1533-4406. PMID 15575056.
- ↑ Lin, Liang-In; et al. (2005). "Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells". Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 11 (4): 1372–1379. doi:10.1158/1078-0432.CCR-04-1816. ISSN 1078-0432. PMID 15746035.
- ↑ Green, Claire L.; et al. (2013). "GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations". British Journal of Haematology. 161 (5): 701–705. doi:10.1111/bjh.12317. ISSN 1365-2141. PMID 23560626.
- ↑ McNagny, K. M.; et al. (1998). "Regulation of eosinophil-specific gene expression by a C/EBP-Ets complex and GATA-1". The EMBO journal. 17 (13): 3669–3680. doi:10.1093/emboj/17.13.3669. ISSN 0261-4189. PMC 1170703. PMID 9649437.
- ↑ Zhang, D. E.; et al. (1997). "Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice". Proceedings of the National Academy of Sciences of the United States of America. 94 (2): 569–574. doi:10.1073/pnas.94.2.569. ISSN 0027-8424. PMC 19554. PMID 9012825.CS1 maint: PMC format (link)
- ↑ Radomska, H. S.; et al. (1998). "CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors". Molecular and Cellular Biology. 18 (7): 4301–4314. doi:10.1128/mcb.18.7.4301. ISSN 0270-7306. PMC 109014. PMID 9632814.CS1 maint: PMC format (link)
- ↑ Zhang, P.; et al. (1998). "Upregulation of interleukin 6 and granulocyte colony-stimulating factor receptors by transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha) is critical for granulopoiesis". The Journal of Experimental Medicine. 188 (6): 1173–1184. doi:10.1084/jem.188.6.1173. ISSN 0022-1007. PMC 2212540. PMID 9743535.
- ↑ Fazi, Francesco; et al. (2005). "A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis". Cell. 123 (5): 819–831. doi:10.1016/j.cell.2005.09.023. ISSN 0092-8674. PMID 16325577.
- ↑ Zhang, Pu; et al. (2004). "Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha". Immunity. 21 (6): 853–863. doi:10.1016/j.immuni.2004.11.006. ISSN 1074-7613. PMID 15589173.
- ↑ Pedersen, T. A.; et al. (2001). "Cooperation between C/EBPalpha TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation". Genes & Development. 15 (23): 3208–3216. doi:10.1101/gad.209901. ISSN 0890-9369. PMC 312836. PMID 11731483.CS1 maint: PMC format (link)
- ↑ Slomiany, B. A.; et al. (2000). "C/EBPalpha inhibits cell growth via direct repression of E2F-DP-mediated transcription". Molecular and Cellular Biology. 20 (16): 5986–5997. doi:10.1128/mcb.20.16.5986-5997.2000. ISSN 0270-7306. PMC 86075. PMID 10913181.CS1 maint: PMC format (link)
- ↑ Timchenko, N. A.; et al. (1996). "CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein". Genes & Development. 10 (7): 804–815. doi:10.1101/gad.10.7.804. ISSN 0890-9369. PMID 8846917.
- ↑ Wang, H.; et al. (2001). "C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4". Molecular Cell. 8 (4): 817–828. doi:10.1016/s1097-2765(01)00366-5. ISSN 1097-2765. PMID 11684017.
- ↑ Wang, Qian-Fei; et al. (2003). "Cell cycle inhibition mediated by the outer surface of the C/EBPalpha basic region is required but not sufficient for granulopoiesis". Oncogene. 22 (17): 2548–2557. doi:10.1038/sj.onc.1206360. ISSN 0950-9232. PMID 12730669.
- ↑ Johansen, L. M.; et al. (2001). "c-Myc is a critical target for c/EBPalpha in granulopoiesis". Molecular and Cellular Biology. 21 (11): 3789–3806. doi:10.1128/MCB.21.11.3789-3806.2001. ISSN 0270-7306. PMC 87031. PMID 11340171.CS1 maint: PMC format (link)
- ↑ Porse, B. T.; et al. (2001). "E2F repression by C/EBPalpha is required for adipogenesis and granulopoiesis in vivo". Cell. 107 (2): 247–258. doi:10.1016/s0092-8674(01)00516-5. ISSN 0092-8674. PMID 11672531.
- ↑ Nanri, Tomoko; et al. (2010). "A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation". Genes, Chromosomes & Cancer. 49 (3): 237–241. doi:10.1002/gcc.20734. ISSN 1098-2264. PMID 19953636.
- ↑ Sellick, G. S.; et al. (2005). "Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia". Leukemia. 19 (7): 1276–1278. doi:10.1038/sj.leu.2403788. ISSN 0887-6924. PMID 15902292.
Notes
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