Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function.

Abstract

B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre-B cell receptor-dependent stages. The Philadelphia chromosome-positive (Ph(+)) subtype of ALL accounts for 25-30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre-B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph(+) ALL cells. Pre-B cell receptor-mediated cell cycle arrest in Ph(+) ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre-B cell receptor signaling pathway, even if expression of the pre-B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre-B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph(+) ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre-B cell receptor-mediated tumor suppression.

• Authors: Daniel Trageser, Ilaria Iacobucci, Rahul Nahar, Cihangir Duy, Gregor von Levetzow, Lars Klemm, Eugene Park, Wolfgang Schuh, Tanja Gruber, Sebastian Herzog, Yong-mi Kim, Wolf-Karsten Hofmann, Aihong Li, Clelia Tiziana Storlazzi, Hans-Martin Jäck, John Groffen, Giovanni Martinelli, Nora Heisterkamp, Hassan Jumaa, Markus Müschen
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 206 Issue 8 Pg. 1739-53 (Aug 03 2009) ISSN: 1540-9538 [Electronic] United States
• PMID: 19620627 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• B cell linker protein
• IKZF1 protein, human
• Pre-B Cell Receptors
• Ikaros Transcription Factor

Topics

• Adaptor Proteins, Signal Transducing (physiology)
• Adult
• Animals
• Cell Cycle
• Cell Transformation, Neoplastic (genetics, immunology)
• Down-Regulation
• Gene Deletion
• Genes, abl
• Humans
• Ikaros Transcription Factor (deficiency, genetics, physiology)
• Leukemia, Prolymphocytic, B-Cell (genetics, pathology, physiopathology)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Philadelphia Chromosome
• Pre-B Cell Receptors (deficiency, genetics, physiology)
• Signal Transduction