Acute myeloid leukemia with t(4;12)(q12;p13): an aggressive disease with frequent involvement of PDGFRA and ETV6

Abstract

We describe the clinical, morphologic, immunophenotypic and molecular genetic features of 15 cases of acute myeloid leukemia (AML) with t(4;12)(q12;p13). There were 9 men and 6 women, with a median age of 50 years (range, 17-76). Most patients had hypercellular bone marrow with a median blast count of 58% and multilineage dysplasia. Flow cytometry analysis showed myeloid lineage with blasts positive for CD13, CD33, CD34, CD38, CD117 and HLA-DR. Interestingly, aberrant CD7 expression was detected in 12/14 cases, and myeloperoxidase was either negative (3/15) or positive in only a small subset of the blasts (12/15). t(4;12)(q12;p13) was detected at time of initial diagnosis in 4 and at relapse or progression in 9 patients. The initial karyotype was unknown in 2 cases. FISH analysis showed PDGFRA-ETV6 rearrangement in all 7 cases assessed. FLT3 ITD was detected in 2/11 cases and IDH2 and JAK2 mutation were each detected in 1/2 cases assessed. There were no mutations of KRAS (0/8), NRAS (0/8), CEBPA (0/3), KIT (0/3), NPM1 (0/3) or IDH1 (0/2). All patients received aggressive multiagent chemotherapy; 7 patients additionally received stem cell transplantation. With a median follow-up of 10 months (range, 6-51), 13 patients died of AML, 1 patient had persistent disease, and 1 patient was lost to follow-up. In summary, AML with t(4;12)(q12;p13) is usually associated with myelodysplasia, aberrant CD7 expression, weak of absent myeloperoxidase expression, frequent PDGFRA-ETV6 fusion, and an aggressive clinical course. The molecular findings suggest that there may be a role for tyrosine kinase inhibitors in patient management.

Keywords: ETV6; PDGFRA; acute myeloid leukemia; t(4;12)(q12;p13).

Figure 1. Morphologic features of AML with t(4;12)(q12;p13) (case 5)

(A). The bone marrow core biopsy shows a hypercellular bone marrow with dysplastic megakaryocytes and increased immature cells (H&E, x400). (B). The aspirate smear shows dysgranulopoiesis and increased blasts (Wright-Giemsa, x1000). (C). The aspirate smear shows dyserythropoiesis and increased blasts (Wright-Giemsa, x1000). (D). The aspirate smear shows numerous blasts that are small to intermediate in size with fine chromatin, occasional prominent nucleoli, and scant basophilic cytoplasm (Wright-Giemsa, x500).

Figure 2. Cytogenetic findings (case 11)

(A). Chromosomal analysis shows a karyotype of 46,XY,t(4;12)(q12;p13)[20]. (B). FISH analysis using PDGFRA tri-color break-apart probe (FIP1L1 in green, CHIC2 in red and PDGFRA in aqua) shows 1 triple fusion, 1 green-red fusion, and 1 separate aqua signal, which confirms PDGFRA gene rearrangement (translocation of aqua signal to derivative chromosome 12). (C). FISH analysis using ETV6 dual-color break-apart probe shows ETV6 gene rearrangement (translocation of red signal to derivative chromosome 4).