Chromosomal Aberration t(14;17)(q32;q21) Simultaneously Activates HOXB5 and miR10a in Triple-Hit B-Cell Lymphoma

<i>BCL2</i>, <i>BCL6</i> and <i>MYC</i> are major oncogenes in B-cell lymphoma. Their aberrant activation frequently occurs via chromosomal translocations which juxtapose light or heavy chain immunoglobulin (IG) genes to <i>BCL2</i> and <i>MYC</i> or fuse diverse partner genes with <i>BCL6</i>. So-called double-hit lymphomas usually carry <i>BCL2</i> and <i>MYC</i> rearrangements, while triple-hit lymphomas additionally bear <i>BCL6</i>-fusions. All these translocations are of diagnostic relevance and usually denote poor prognosis. Here, we genomically characterized classic follicular lymphoma (FL) cell line SC-1, thereby identifying t(14;18)(q32;q21) juxtaposing <i>IGH</i> and <i>BCL2</i>, t(8;14)(q24;q32) juxtaposing <i>IGH</i> and <i>MYC</i>, and t(3;3)(q25;q27) fusing <i>MBNL1</i> to <i>BCL6</i>. In addition, we found that SC-1 carries a novel chromosomal rearrangement, t(14;17)(q32;q21), which, though present at establishment, has remained unreported until now. We further show that t(14;17)(q32;q21) juxtaposes <i>IGH</i> with the HOXB gene cluster at 17q21 and affect the oncogenic activation of both homeobox gene <i>HOXB5</i> and neighboring micro-RNA gene <i>miR10a</i>. Moreover, we detected aberrant overexpression of <i>HOXB5</i> in subsets of Burkitt lymphoma, FL, and multiple myeloma patients, confirming the clinical relevance of its deregulation. In SC-1, <i>HOXB5</i> activation was additionally supported by co-expression of hematopoietic stem cell factor ZNF521, indicating an aberrant impact in cell differentiation. Functional investigations showed that HOXB5 represses the apoptotic driver <i>BCL2L11</i> and promotes survival in the presence of etoposide, and that <i>miR10a</i> inhibits BCL6 and may thus play an oncogenic role in later stages of lymphomagenesis. Collectively, we characterize triple-hit B-cell line SC-1 and identify the aberrant expression of <i>HOXB5</i> and <i>miR10a</i>, both novel oncogenes in B-cell lymphoma.