Bone Marrow Histopathology in 8 Patients with Myeloid Neoplasms and PRDM16 Translocations: Analysis Reveals Recurring Dysplastic Features
Linda N Dao, Ryan A Knudson, Rhett P Ketterling, William R Sukov. Mayo Clinic, Rochester, MN
Background: In myeloid malignancies, specific chromosomal alterations have been associated with particular histologic and clinical features. Inversion of chromosome 3 resulting in fusion of EVI1 (3q26.2) and RPN1 (3q21) has been associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with elevated platelet counts and atypical megakaryocytes. PRDM16 (1p36.3) is a homolog of EVI1 and can be rearranged with RPN1 to result in PRDM16 upregulation. Other rarer partner genes with PRDM16 have also been described. These translocations are seen in several myeloid neoplasms including MDS, myelodysplastic/myeloproliferative neoplasms and AML.
Design: Patient bone marrow (BM) samples with abnormal chromosome results with rearrangements of the PRDM16 locus at 1p36.3 were identified. A home-brew break-apart (BAP) FISH probe was developed from BAC clones to detect rearrangement of PRDM16 and all candidate patient samples were tested. Home-brew FISH probes employing a dual-color, double-fusion (D-FISH) strategy was developed to confirm PRDM16/RPN1 fusion. For each patient, associated peripheral blood, BM aspirates and biopsies were reviewed to define histopathologic features.
Results: Eight patients (2 females, 6 males) with peripheral blood and BM evaluations were identified by FISH as having rearrangements of PRDM16. Of these, five patients had t(1;3)(p36.3;q21) resulting in PRDM16/RPN1 fusion. Three patients had a rearrangement of PRDM16 by FISH resulting in fusion with an unknown partner gene at chromosome 2p21, 1q21 and 8q22. Histologically, BM biopsies from seven patients had dysplastic features, all with dysmegakaryopoiesis. One patient's BM was replaced by leukemic blasts and background hematopoiesis could not be evaluated. One patient had peripheral monocytosis and increased monocytic cells in the bone marrow. One other patient had increased peripheral blood monocytes but absolute monocytosis could not be confirmed due to lack of a completed blood count.
Conclusions: Translocations involving PRDM16 typically involve fusion with the RPN1 promoter; however other unknown genes, including genes at 2p21, 1q21 and 8q22, are infrequently partnered with PRDM16. Rearrangements of PRDM16 are associated with myeloid neoplasms with dysplastic features, in particular dysmegakaryopoiesis. Monocytosis can be identified but is not a consistent feature in these patients. FISH testing can be helpful to specifically identify involvement of PRMD16 in patients with myeloid neoplasms and clonal abnormalities involving 1p36.3.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 239, Tuesday Morning