IMMORTALIZATION AND LEUKEMIC TRANSFORMATION OF A MYELOMONOCYTIC PRECURSOR BY RETROVIRALLY TRANSDUCED HRX-ENL

A subset of chromosomal translocations in acute leukemias results in t he fusion of the trithorax-related protein HRX with a variety of heter ologous proteins. In particular, leukemias with the t(11;19)(q23;p13.3 ) translocation express HRX-ENL fusion proteins and display features w hich suggest the malignant transformation of myeloid and/or lymphoid p rogenitor(s). To characterize directly the potential transforming effe cts of HRX-ENL on primitive hematopoietic precursors, the fusion cDNA was transduced by retroviral gene transfer into cell populations enric hed in hematopoietic stem cells, The infected cells had a dramatically enhanced potential to generate myeloid colonies,vith primitive morpho logy in vitro. Primary colonies could be replated for at least three g enerations in vitro and established primitive myelomonocytic cell line s upon transfer into suspension cultures supplemented with interleukin -3 and stem cell factor, Immortalized cells contained structurally int act HRX-ENL proviral DNA and expressed a low-level of HRX-ENL mRNA. In contrast, wild-type ENL or a deletion mutant of HRX-ENL lacking the E NL component did not demonstrate in vitro transforming capabilities. I mmortalized cells or enriched primary hematopoietic stem cells transdu ced with HRX-ENL induced myeloid leukemias in syngeneic and SCID recip ients, These studies demonstrate a direct role for HRX-ENL in the immo rtalization and leukemic transformation of a myeloid progenitor and su pport a gain-of-function mechanism for HRX-ENL-mediated leukemogenesis .