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Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis
Ryoichi Ono, … , Yasuhide Hayashi, Tetsuya Nosaka
Ryoichi Ono, … , Yasuhide Hayashi, Tetsuya Nosaka
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):919-929. https://doi.org/10.1172/JCI22725.
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Article Hematology

Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis

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Abstract

The mechanisms by which mixed-lineage leukemia (MLL) fusion products resulting from in utero translocations in 11q23 contribute to leukemogenesis and infant acute leukemia remain elusive. It is still controversial whether the MLL fusion protein is sufficient to induce acute leukemia without additional genetic alterations, although carcinogenesis in general is known to result from more than 1 genetic disorder accumulating during a lifetime. Here we demonstrate that the fusion partner–mediated homo-oligomerization of MLL-SEPT6 is essential to immortalize hematopoietic progenitors in vitro. MLL-SEPT6 induced myeloproliferative disease with long latency in mice, but not acute leukemia, implying that secondary genotoxic events are required to develop leukemia. We developed in vitro and in vivo model systems of leukemogenesis by MLL fusion proteins, where activated FMS-like receptor tyrosine kinase 3 (FLT3) together with MLL-SEPT6 not only transformed hematopoietic progenitors in vitro but also induced acute biphenotypic or myeloid leukemia with short latency in vivo. In these systems, MLL-ENL, another type of the fusion product that seems to act as a monomer, also induced the transformation in vitro and leukemogenesis in vivo in concert with activated FLT3. These findings show direct evidence for a multistep leukemogenesis mediated by MLL fusion proteins and may be applicable to development of direct MLL fusion–targeted therapy.

Authors

Ryoichi Ono, Hideaki Nakajima, Katsutoshi Ozaki, Hidetoshi Kumagai, Toshiyuki Kawashima, Tomohiko Taki, Toshio Kitamura, Yasuhide Hayashi, Tetsuya Nosaka

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Figure 1

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Immortalization of murine hematopoietic progenitors by MLL-SEPT6 fusion ...
Immortalization of murine hematopoietic progenitors by MLL-SEPT6 fusion protein via aberrant expression of Hox genes. (A) Schematic representation of the retroviral constructions used. CXXC, CXXC domain; Zn fingers, zinc fingers; CS, cleavage sites; TAD, transactivation domain; SET, SET domain. (B) Western blot analysis of proteins extracted from PlatE cells transfected with the constructs shown in A, after immunoprecipitation using the anti-MLL Ab (lanes 1–9). Each lysate was blotted with the anti-FLAG Ab (lanes 1–9) or anti-SEPT6 Ab (lanes 10 and 11). Endogenous expression of SEPT6 was detected in lane 10. Lane 1, mock; lane 2, 5′-MLL; lane 3, MLL-SEPT6; lane 4, MLL-SEPT6Δcoil; lane 5, MLL-SEPT6Δcoil-ER; lane 6, MLL-SEPT6ΔGTP; lane 7, MLL-SEPT6ΔP-loop; lane 8, MLL-SEPT6S56N; lane 9, MLL-ENLs; lane 10, pMXs-neo alone (endogenous SEPT6); lane 11, SEPT6. (C) Experimental strategy for myeloid immortalization assay. (D) Myeloid immortalization assay using the constructs shown in A. Lanes for MLL-SEPT6Δcoil-ER indicate the presence (+) or absence (–) of 4-OHT. The bar graph shows numbers of colonies obtained after each round of replating in methylcellulose (average ± SD). (E and F) Typical morphology of the colonies generated by MLL-SEPT6 (E), and the cells constituting these colonies (F). Original magnification, ×40 (E), ×400 (F). (G) Expression of Hox a7, Hox a9, and Meis1 by RT-PCR in the cells from third-round cultures. β2m was used as an internal standard. M, 100-bp DNA ladder (New England Biolabs Inc.); lane 1, control (Ba/F3 with IL-3) cells; lane 2, mock; lane 3, MLL-SEPT6; lane 4, MLL-ENLs; lane 5, negative control.

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