First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation

Abstract

Donor cell leukemia after allogeneic hematopoietic stem cell transplantation might provide a unique human model for our understanding of leukemogenesis in vivo. We hypothesized that the "2-genetic-hits model" may contribute to the "leukemization" of donor cells and first evaluated these genetic mutations that are implicated in the development of acute myeloid leukemia in a donor cell leukemia patient and donor. The patient and his donor-sister both harbored a germline mutation in CEBPA (584_589dup). Susceptible donor hematopoietic cells evolved to overt acute myeloid leukemia by developing 2 somatic CEBPA mutations (247dupC and 914_916dup) in the patient's microenvironment. These were identical to the acquired mutations identified in leukemic cells that originated from the patient during de novo acute myeloid leukemia. Our results provide the first report of multiple mutations of CEBPA contributing to the transformation of donor cells to the leukemic phenotype and provide clues to support the multiplegenetic-hits mechanism of donor cell leukemia. (Blood. 2011;117(19):5257-5260) IntroductionLeukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) that arises in cells of donor origin in the transplant recipient, so-called donor cell leukemia (DCL), is a rare disease entity, and only 51 cases were reported since 1971. [1][2][3][4] The precise etiologic mechanisms of DCL remain unknown, and no common mechanism can be identified in most of the cases reported in the literature. Careful analysis of the mechanisms with respect to the oncogenic transformation of donor-derived cells might provide a unique human model for our understanding of leukemogenesis in vivo.According to the "2-genetic-hits model," cooperation between 2 classes of genetic mutations contributes to leukemogenesis. 5 One group (class 1) comprises mutations in the fms-related tyrosine kinase 3 gene (FLT3) or the neuroblastoma RAS viral oncogene homolog gene (NRAS), which increase the proliferation and/or survival of hematopoietic stem/progenitor cells. 6,7 The other complementation group (class 2) comprises mutations in CEBPA, the gene that encodes the CCAAT enhancer-binding protein␣ (C/EBP␣); the myeloid-lymphoid or mixed-lineage leukemia gene (MLL); or the nucleophosmin gene (NPM1), which cause impaired differentiation. [8][9][10] The most common mutations, which include internal tandem duplications restricted to exons 14 and 15 and point mutation of Asp 835 within the TK domain of FLT3, codon 12/13 in exon 1 and codon 61 in exon 2 of NRAS, the entire coding region of CEBPA, partial tandem duplications that span exons 2-6 or exons 2-8 of MLL, and mutations in exon 12 of NPM1, have been described extensively in acute myeloid leukemia (AML). [11][12][13][14] We hypothesized that the 2-genetic-hits model may contribute to the "leukemization" of donor cells in DCL. We screened these genetic mutations implicated in the development of common forms of AML in a DCL patient and donor. MethodsThe study was approved by the Zhejiang U...

Acute myeloid leukemia of donor origin after allogeneic stem cell transplantation from a sibling who harbors germline XPD and XRCC3 homozygous polymorphisms

“…Indeed, this is further supported by the observation of a switch from normal to highly abnormal post-SCT of the patient's karyotype and FISH analysis. This supports the theory that in donor origin leukemia, the host environment in which the original malignancy developed could trigger an oncogenic process in donor cells, favored by the immunosuppressive status after transplantation, especially because the donor is still healthy [31,32]. …”

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

“…Inadvertent transplantation with stem cells from a sibling donor carrying an unrecognized germline predisposition syndrome can lead to devastating complications including failure to engraft, severe transplant-related toxicity, and the development of donor-derived leukemia [26–30]. Longer term implications of having an underlying predisposition syndrome frequently include an increased risk of non-hematologic malignancies, particularly in disorders such as Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) [22,31,32].…”

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

“…[2][3][4][5][6][7][8][9][10][11][12][13] Studies of large series of normal-karyotype AML have reported a frequency of CEBPA mutation of 8% to 13% 4,8,14 ; among these, 7% to 11% have germline CEBPA mutations. 4,8 The majority of the AML patients have 2 CEBPA mutations with both N-terminal frameshift mutation and C-terminal inframe mutation on different alleles.…”