Diagnosis -- Acute myeloid leukemia (AML) with CEBPA mutation

FINAL DIAGNOSIS

Acute myeloid leukemia (AML) with CEBPA mutation.

DISCUSSION

Based on the 2022 WHO classification, AML with CEBPA mutation falls under the diagnostic category of AML with defining genetic abnormalities. These specific cases are typically characterized by biallelic mutations involving the CEBPA gene, however cases involving single mutations of the basic leucine zipper region on a single allele have also been reported (see Figure 3) [1]. CEBPA encodes a transcription factor that binds to the promoter of multiple myeloid-related genes to promote myeloid differentiation. Knockout studies in mice show that deactivation of CEBPA causes cells to arrest at the common myeloid progenitor phase of development [2].

Analysis of CEBPA mutant AML shows that most cases involve an out-of-frame mutation in the N-terminus of one allele, often with an in-frame C-terminus mutation in the other allele [2]. A subset of bi-allelic CEBPA mutant AML cases may harbor germline mutations in the N-terminal region of one allele with subsequent development of acquired somatic mutations involving the C-terminal region of the other allele. Germline CEBPA mutations are associated with familial AML and are often highly penetrant. They also carry a high risk of relapse due to additional acquired C-terminus mutations resulting in new neoplastic clones [4].

Investigation by the Children's Oncology Group revealed that roughly 5% of pediatric AML cases harbor mutations in the basic leucine zipper region of the CEBPA gene (CEBPA-bZip), and that over 80% of these cases also harbor a second CEBPA mutation (CEBPA-dm). Both the CEBPA-bZip and CEBPA-dm cohorts demonstrated superior overall survival compared to CEBPA-wild-type AML. Interestingly, the co-occurrence of CSF3R mutation was observed in 10-15% of CEBPA mutated cases and was found to negate the survival benefit typically associated with CEBPA mutant AML [5].

The introduction of molecular testing has led to the expansion of an entire category of acute myeloid leukemias known as AML with defining genetic abnormalities. In addition to AML with CEBPA mutation, other entities within this category are highlighted in the table below (see Table 1)

Table 1: Acute myeloid leukemia with defining genetic abnormalities and their associated prognoses, adapted from [6].

REFERENCES

1. Fogelstrand, Linda, et al. "Acute Myeloid Leukaemia with CEBPA Mutation." WHO Classification of Tumours Online, Haematolymphoid Tumours, 5th ed., International Agency for Research on Cancer, Lyon , France, 2022.
2. Avellino R, Delwel R. Expression and regulation of C/EBP? in normal myelopoiesis and in malignant transformation. Blood. 2017 Apr 13;129(15):2083-2091. doi: 10.1182/blood-2016-09-687822. Epub 2017 Feb 8. PMID: 28179278.
3. Ethan Cerami, Jianjiong Gao, Ugur Dogrusoz, Benjamin E. Gross, Selcuk Onur Sumer, Bülent Arman Aksoy, Anders Jacobsen, Caitlin J. Byrne, Michael L. Heuer, Erik Larsson, Yevgeniy Antipin, Boris Reva, Arthur P. Goldberg, Chris Sander, Nikolaus Schultz; The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discov 1 May 2012; 2 (5): 401-404. https://doi.org/10.1158/2159-8290.CD-12-0095
4. Tawana K, Wang J, Renneville A, Bödör C, Hills R, Loveday C, Savic A, Van Delft FW, Treleaven J, Georgiades P, Uglow E, Asou N, Uike N, Debeljak M, Jazbec J, Ancliff P, Gale R, Thomas X, Mialou V, Döhner K, Bullinger L, Mueller B, Pabst T, Stelljes M, Schlegelberger B, Wozniak E, Iqbal S, Okosun J, Araf S, Frank AK, Lauridsen FB, Porse B, Nerlov C, Owen C, Dokal I, Gribben J, Smith M, Preudhomme C, Chelala C, Cavenagh J, Fitzgibbon J. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015 Sep 3;126(10):1214-23. doi: 10.1182/blood-2015-05-647172. Epub 2015 Jul 10. PMID: 26162409.
5. Tarlock K, Lamble AJ, Wang Y-C, et al. CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group. Blood. 2021;138(13):1137-1147. Blood. 2022 Mar 10;139(10):1601. doi: 10.1182/blood.2022015692. Erratum for: Blood. 2021 Sep 30;138(13):1137-1147. PMID: 35266998; PMCID: PMC9211438.
6. "Acute myeloid leukaemia with defining genetic abnormalities." WHO Classification of Tumours Online, Haematolymphoid Tumours, 5th ed., International Agency for Research on Cancer, Lyon , France, 2022.

Contributed by Simmi Patel, MD and Rana Naous, MD