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An intronic deletion in megakaryoblastic leukemia 1 is associated with hyperproliferation of B cells in triplets with Hodgkin lymphoma

Record, J; Sendel, A; Kritikou, JS; Kuznetsov, NV; Brauner, H; He, M; Nagy, N; ... Westerberg, LS; + view all (2019) An intronic deletion in megakaryoblastic leukemia 1 is associated with hyperproliferation of B cells in triplets with Hodgkin lymphoma. Haematologica 10.3324/haematol.2019.216317. (In press). Green open access

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Abstract

Megakaryoblastic leukemia 1 (MKL1) is a coactivator of serum response factor and 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. To investigate MKL1 and B cell responses in HL pathogenesis, we generated Epstein Barr virus-transformed lymphoblastoid cell lines from the triplets and two controls. While cells from the Hodgkin lymphoma 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. Moreover, cells from the undiagnosed triplet proliferated faster, displayed a higher proportion of cells with hyperploidy, and formed large tumors in vivo. This phenotype was reversible by inhibiting MKL1 activity. Interestingly, cells from the triplet treated for Hodgkin lymphoma 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. This implies that pre-malignant cells had re-emerged a long time after treatment. Together, these data suggest that dysregulated MKL1 activity participates in B cell transformation and Hodgkin lymphoma pathogenesis.

Type: Article
Title: An intronic deletion in megakaryoblastic leukemia 1 is associated with hyperproliferation of B cells in triplets with Hodgkin lymphoma
Location: Italy
Open access status: An open access version is available from UCL Discovery
DOI: 10.3324/haematol.2019.216317
Publisher version: https://doi.org/10.3324/haematol.2019.216317
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Megakaryoblastic leukemia 1 (MKL1), Hodgkin lymphoma (HL), B cells, actin cytoskeleton
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10083174
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