BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros

Abstract

The Philadelphia chromosome, a chromosomal abnormality that encodes BCR-ABL1, is the defining lesion of chronic myelogenous leukaemia (CML) and a subset of acute lymphoblastic leukaemia (ALL). To define oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed a genome-wide analysis of diagnostic leukaemia samples from 304 individuals with ALL, including 43 BCR-ABL1 B-progenitor ALLs and 23 CML cases. IKZF1 (encoding the transcription factor Ikaros) was deleted in 83.7% of BCR-ABL1 ALL, but not in chronic-phase CML. Deletion of IKZF1 was also identified as an acquired lesion at the time of transformation of CML to ALL (lymphoid blast crisis). The IKZF1 deletions resulted in haploinsufficiency, expression of a dominant-negative Ikaros isoform, or the complete loss of Ikaros expression. Sequencing of IKZF1 deletion breakpoints suggested that aberrant RAG-mediated recombination is responsible for the deletions. These findings suggest that genetic lesions resulting in the loss of Ikaros function are an important event in the development of BCR-ABL1 ALL.

Long-Range Epigenetic Silencing Associates with Deregulation of Ikaros Targets in Colorectal Cancer Cells

“…These factors are characteristic of the hematopoietic system and are specifically expressed at different stages of the lymphoid branch. Recent studies highlight the importance of genetic alterations undergone by Ikaros family members in various hematologic neoplasias (13)(14)(15).…”

Presence of CD34+CD38−CD58− leukemia-propagating cells at diagnosis identifies patients at high risk of relapse with Ph chromosome-positive ALL after allo-hematopoietic SCT

“…38,39 In the present cohort study, IKZF1-deletions were analyzed in 52.5% of the subjects, which made it difficult to directly compare the impact of the LPC phenotype or IKZF1-deletions on post-HSCT outcomes. It should be noted, however, that our preliminary results demonstrated that the frequency of IKZF1-deletions at diagnosis were comparable between the two phenotypic groups, which emphasizes the prognostic significance of the LPC phenotype.…”

Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL

“…Mice with germline mutations that inactivate the transcriptional regulator Ikaros (gene symbol Ikzf1) develop T-ALL exclusively [23,25] and the resulting malignancies often have activating NOTCH1 mutations [6,23,24]. Ikzf1 somatic mutations are also frequently found in combination with NOTCH1 mutations in mouse retrovirus-promoted T-ALL [18] and in human B-ALL and T-ALL [26,27]. Short, dominant negative forms of Ikaros generated by alternative splicing have also been found in human T-ALL [28,29] although this has not been found in other T-ALL series [30].…”