MN1–Fli1 oncofusion transforms murine hematopoietic progenitor cells into acute megakaryoblastic leukemia cells

Abstract

Long-term outcome of acute megakaryoblastic leukemia (AMKL) patients without Down's syndrome remains poor. Founding mutations and chimeric oncogenes characterize various AMKL subtypes. However, for around one third of all cases the underlying mechanisms of AMKL leukemogenesis are still largely unknown. Recently, an in-frame fusion of meningeoma 1–friend leukemia virus integration 1 (MN1–Fli1) gene was detected in a child with AMKL. We intended to investigate the potential role of this oncofusion in leukemogenesis of acute myeloid leukemia. Strikingly, expression of MN1–Fli1 in murine hematopoietic progenitor cells was sufficient to induce leukemic transformation generating immature myeloid cells with cytomorphology and expression of surface markers typical for AMKL. Systematic structure function analyses revealed FLS and 3′ETS domains of Fli1 as decisive domains for the AMKL phenotype. Our data highlight an important role of MN1–Fli1 in AMKL leukemogenesis and provide a basis for research assessing the value of this oncofusion as a future diagnostic marker and/or therapeutic target in AMKL patients.

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

“…Retroviral expression of CBFA2T3–GLIS2, GATA2–HOXA9, MN1–FLI1, and NIPBL–HOXB9 allowed serial replating of adult mouse BM-derived hematopoietic cells in MC associated with expression of megakaryocytic markers on some CBFA2T3–GLIS2- and MN1–FLI1-expressing cells. Consistently with the high homology between ERG and FLI1, transplantation of these MN1–FLI1-transduced cells was sufficient for the development of murine leukemia presenting clear features of AMKL (80, 81). However, GATA2–HOXA9- and NIPBL–HOXB9-transduced cells led to penetrant AML phenotypes but with limited megakaryocytic features, and CBFA2T3–GLIS2-transduced cells did not induce any disease (81).…”

Ectopia associated MN1 fusions and aberrant activation in myeloid neoplasms with t(12;22)(p13;q12)

“…Besides, MN1 has been reported significantly upregulated in ETV6-AML1-positive B-cell acute lymphoblastic patients [20]. MN1 has also been observed to fuse with another ETS family of transcription factors gene FLI1 in acute megakaryoblastic leukemia [21]. These reports together wellfounded indicate that MN1 overexpression might closely cooperate with abnormalities of transcription-factor genes such as ETV6, CBFB, CEBPA, and FLI1 in leukemogenesis.…”

Leucémies à mégacaryoblastes de l’enfant

“…Sachant que GATA1 interagit avec RB1 et E2F2 afin de réguler la prolifération des progéniteurs érythro-mégacaryocytaires [36], il apparaît important de définir si le rôle des mutations inactivatrices de RB1 dans la leucémogenèse des LAM7 a un lien avec l'activité ( Figure 1, groupe Autres) montre l'implication directe des facteurs de la famille ETS, ERG et FLI1, qui présentent une forte homologie de séquence et de fonction [29]. Dans le cas de MN1-FLI1, les capacités d'autorenouvellement des progéniteurs murins in vitro et le phénotype mégacaryocytaire sont contrôlés par le domaine FLI1 de la molécule de fusion [30]. D'autres mutations fréquemment retrouvées dans les différents sous-groupes de LAM7 participent aux modifications d'activités d'ERG.…”