Acute Myeloid Leukemia (AML) with Biallelic Mutations of CEBPA
Paul Defazio, MSc, Monash Health
Acute Myeloid Leukemia (AML)
Cancer Sub-Classification / Subtype
Acute myeloid leukaemia (AML) with biallelic CEBPA mutations
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.
Mutations in CEBPA have been divided into two types. 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. 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.
Synonyms / Terminology
Epidemiology / Prevalence
Approximately 6-15% of de novo AML and 15-18% of AML with normal karyotypes have monoallelic or biallelic CEBPA mutations. 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. Inherited CEBPA are associated with earlier-onset AML. Taskesen et al. reported that five of 71 (7%) CEBPA-mutant AML patients carried germline mutations.
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. There is also a lower frequency of lymphadenopathy and myeloid sarcoma in CEBPA mutated AML than in non-mutated AML.
Sites of Involvement
Blood, bone marrow
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.
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. 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.
|Positive (universal)||EXAMPLE CD1|
|Positive (subset)||EXAMPLE CD2|
|Negative (universal)||EXAMPLE CD3|
|Negative (subset)||EXAMPLE CD4|
Chromosomal Rearrangements (Gene Fusions)
|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%|
Characteristic Chromosomal Aberrations / Patterns
|EXAMPLE 8||EXAMPLE Gain||EXAMPLE chr8:0-1000000|
|EXAMPLE 7||EXAMPLE Loss||EXAMPLE chr7:0-1000000|
Gene Mutations (SNV/INDEL)
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)|
Concurrent mutations in NPM1 and FLT3 are seen less frequently in individuals with biallelic CEBPA mutations than in those with no or monoallelic mutations. Conversely, mutations in GATA2 appear to occur more often in CEBPA single- and double-mutants. The prognostic significance of these concomitant mutations is, however, unclear. Biallelic CEBPA mutations appear to confer a positive prognostic effect regardless of concomitant mutations.
|Concomitant Mutations||NPM1, FLT3, GATA2|
Genes and Main Pathways Involved
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. CEBPA knockout mice show a complete lack of granulocytes while blasts accumulate in the bone marrow, suggesting an early block of myeloid maturation. 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). It has also been implicated, along with NFI-A, in mediating miR-223 expression. 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. 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. This E2F inhibition leads to c-myc downregulation, which is required for granulocytic regulation. Mutations in the C-terminal region of CEBPA abrogate CEBPA-E2F complex function. The precise mechanism by which CEBPA mutants inhibit granulocytic differentiation in the context of AML is still unclear.
Diagnostic Testing Methods
Sanger sequencing, Next Generation Sequencing
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
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. 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.
Familial mutations of CEBPA have been described in several families. Typically, these are N-terminal mutations that are later joined by a somatic C-terminal mutation on the opposite allele leading to AML.
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