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.

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

“…To test whether SLP65 is also required for Igβ signaling, we generated HLSLP65 triple KO Ramos B cells and verified the loss of SLP65 expression by Western blot (Appendix Fig S5). The cells were then transduced with plasmids encoding SLP65ERT2, a tamoxifen‐inducible form of SLP65 (Trageser et al , 2009). Upon exposure to anti‐Igβ and tamoxifen, the SLP65ERT2‐transduced HLSLP65 triple KO Ramos cells showed a calcium flux, whereas cells lacking SLP65ERT2 display no change in the calcium level (Fig 4B).…”

Genomic profiling of high-risk acute lymphoblastic leukemia

“…45 Moreover, deletion of Ikzf1 accelerates leukemogenesis in a murine model of Ph þ ALL. 26 A role for IKAROS in the pathogenesis of ALL is also supported by recent data from genome-wide association studies in which an inherited single-nucleotide polymorphism allele at the IKZF1 locus was associated with the risk of childhood ALL, a finding that has been identified in multiple studies and patient cohorts.…”

IKAROS isoform 6 enhances BCR-ABL1-mediated proliferation of human CD34+ hematopoietic cells on stromal cells

“…Although precise mechanism remains to be elucidated, impaired IKAROS function may perturb the differentiation of hematopoietic progenitors that have proliferative and/or survival advantage by BCR-ABL1-mediated signaling. Interestingly, IKAROS was recently reported to behave as tumor suppressor to induce cell cycle arrest in BCR-ABL1 + cells through cooperation with downstream molecules of the pre-B cell receptor signaling pathway, and this effect is reversed by coexpression of IK6 (33).…”