BCL2,BCL6andMYCare major oncogenes in B-cell lymphoma. Their aberrant activation frequently occurs via chromosomal translocations which juxtapose light or heavy chain immunoglobulin (IG) genes toBCL2andMYCor fuse diverse partner genes withBCL6. So-called double-hit lymphomas usually carryBCL2andMYCrearrangements, while triple-hit lymphomas additionally bearBCL6-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) juxtaposingIGHandBCL2, t(8;14)(q24;q32) juxtaposingIGHandMYC, and t(3;3)(q25;q27) fusingMBNL1toBCL6. 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) juxtaposesIGHwith the HOXB gene cluster at 17q21 and affect the oncogenic activation of both homeobox geneHOXB5and neighboring micro-RNA genemiR10a. Moreover, we detected aberrant overexpression ofHOXB5in subsets of Burkitt lymphoma, FL, and multiple myeloma patients, confirming the clinical relevance of its deregulation. In SC-1,HOXB5activation 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 driverBCL2L11and promotes survival in the presence of etoposide, and thatmiR10ainhibits 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 ofHOXB5andmiR10a, both novel oncogenes in B-cell lymphoma.