Julien Record, Sweden
Karolinska Institutet MTCPresenter of 1 Presentation
AN INTRONIC DELETION IN MKL1 IS ASSOCIATED WITH HYPERPROLIFERATION OF B CELLS IN TRIPLETS WITH HODGKIN LYMPHOMA
Abstract
Background and Aims
Megakaryoblastic leukemia-1 (MKL1) is a coactivator of serum response factor that together regulate transcription of actin cytoskeleton genes. MKL1 is associated with hematologic malignancies and immunodeficiency, but its role in B cells is unexplored. Here we examined B cells from monozygotic triplets with an intronic deletion in MKL1, two of whom were previously treated for Hodgkin lymphoma (HL).
Methods
The impact of the intronic deletion in MKL1 was assessed by RT-qPCR, WB, Flow cytometry, microscopy and in vivo assays using EBV-transformed lymphoblastoid cell lines (LCLs) from the triplets and two healthy donors.
Results
While cells from the HL treated patients had a phenotype close to healthy controls, cells from the undiagnosed triplet had increased MKL1 mRNA, increased MKL1 protein, and elevated expression of MKL1-dependent genes. This was associated with elevated actin content, increased cell spreading, decreased expression of CD11a integrin molecules, and delayed aggregation. Cells from the undiagnosed triplet proliferated faster, displayed a higher proportion of cells with genomic instability, and formed large tumors in vivo. This phenotype was reversible by inhibiting MKL1 activity. Interestingly, LCLs from the triplet treated for HL in 1985 contained two subpopulations: one with high expression of CD11a that behaved like control cells and the other with low expression of CD11a that formed large tumors in vivo similar to cells from the undiagnosed triplet.
Conclusions
These results suggest that increasedMKL1 activity leads B cell transformation and HL pathogenesis. Moreover the triplets treated for HL have pro-oncogenic cells that re-emerged a long time after treatment.