A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy

The 2 most frequent human MLL hematopoietic malignancies involve either AF4 or AF9 as fusion partners; each has distinct biology but the role of the fusion partner is not clear. We produced MII-AF4 knock-in (KI) mice by homologous recombination in embryonic stem cells and compared them with MII-AF9 KI mice. Young M11-AF4 mice had lymphoid and myeloid deregulation manifest by increased lymphoid and myeloid cells in hematopoletic organs. In vitro, bone marrow cells from young mice formed unique mixed pro-B lymphold (B220(+)CD19(+)CD43(+)slgM(-), PAX5(+), TdT(+), IgH rearranged)/myeloid (CD11b/Mac1(+), c-fms(+), lysozyme(+)) colonies when grown in IL-7- and Flt3 ligand-containing media. Mixed lymphoid/myeloid hyperplasia and hematologic malignancies (most frequently B-cell lymphomas) developed in MII-AF4 mice after prolonged latency; long latency to malignancy indicates that MII-AF4-induced lymphold/myeloid deregulation alone is insufficient to produce malignancy. In contrast, young MII-AF9 mice had predominately myeloid deregulation in vivo and in vitro and developed myeloid malignancies. The early onset of distinct mixed lymphoid/myelold lineage deregulation in MII-AF4 mice shows evidence for both "instructive" and "noninstructive" roles for AF4 and AF9 as partners in MLL fusion genes. The molecular basis for "instruction" and secondary cooperating mutations can now be studied in our MII-AF4 model.