ArticleThe Journal of clinical investigation2005
Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis.
Article in The Journal of clinical investigation, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 112 citations in OpenAlex.
- Article
- Co-existence ofFrontiers in oncology · 2023Article
- Therapy-related myeloid neoplasms resembling juvenile myelomonocytic leukemia: a case series and review of the literature.Pediatric blood & cancer · 2022Review
- Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia.eLife · 2021Article
- Article
- Review
- A case ofCold Spring Harbor molecular case studies · 2018Article
- De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.Nature communications · 2018Article
- Evolution of AF6-RAS association and its implications in mixed-lineage leukemia.Nature communications · 2017Article
- Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia.Nature genetics · 2017Article
- Eya2, a Target Activated by Plzf, Is Critical forMolecular and cellular biology · 2017Article
- Review
- Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis.Scientific reports · 2016Article
- WDR5 high expression and its effect on tumorigenesis in leukemia.Oncotarget · 2016Article
- Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD).Journal of biochemistry · 2016Review
- Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition.Leukemia · 2015Article
- Molecular mechanisms of MLL-associated leukemia.International journal of hematology · 2015Review
- Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction.Haematologica · 2014Article
- A novel cell-cycle-indicator, mVenus-p27K-, identifies quiescent cells and visualizes G0-G1 transition.Scientific reports · 2014Article
- Septin functions in organ system physiology and pathology.Biological chemistry · 2014Review
3 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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