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E2A‐ PBX 1  is a chimeric gene product detected in t(1;19)‐bearing acute lymphoblastic leukemia ( ALL ) with B‐cell lineage. To investigate the leukemogenic process, we generated conditional knock‐in ( cKI ) mice for  E2A‐ PBX 1 , in which  E2A‐ PBX 1  is inducibly expressed under the control of the endogenous  E2A  promoter. Despite the induced expression of  E2A‐ PBX 1 , no hematopoietic disease was observed, strongly suggesting that additional genetic alterations are required to develop leukemia. To address this possibility, retroviral insertional mutagenesis was used. Virus infection efficiently induced T‐cell, B‐cell, and biphenotypic  ALL  in  E2A‐ PBX 1   cKI  mice. Inverse  PCR  identified eight retroviral common integration sites, in which enhanced expression was observed in the  Gfi1 ,  Mycn , and  Pim1  genes. In addition, it is of note that viral integration and overexpression of the  Zfp521  gene was detected in one tumor with B‐cell lineage; we previously identified  Zfp521  as a cooperative gene with  E2A‐ HLF  , another  E2A ‐involving fusion gene with B‐lineage  ALL . The cooperative oncogenicity of  E2A‐ PBX 1  with overexpressed  Zfp521  in B‐cell tumorigenesis was indicated by the finding that  E2A‐ PBX 1   cKI ,  Zfp521  transgenic compound mice developed B‐lineage  ALL . Moreover, upregulation of   ZNF 521 , the human counterpart of  Zfp521 , was found in several human leukemic cell lines bearing t(1;19). These results indicate that  E2A‐ PBX 1  cooperates with additional gene alterations to develop  ALL . Among them, enhanced expression of   ZNF 521  may play a clinically relevant role in  E2A  fusion genes to develop B‐lineage ALL.

Identification of cooperative genes for E2A‐PBX1 to develop acute lymphoblastic leukemia