Ikzf1 Haploinsufficiency Contributes to the Pathogenesis of BCR-ABL1 Positive Acute Lymphoblastic Leukemia.

Abstract 678

Expression of the constitutively active tyrosine kinase BCR-ABL1 is the hallmark of two diseases with distinct pathologic and clinical features: chronic myeloid leukemia (CML), an expansion of relatively mature granulocytes that typically responds well to kinase inhibition, and pre-B cell acute lymphoblastic leukemia (ALL), an aggressive malignancy of lymphoid progenitors that has a dismal prognosis. The basis for this dichotomy has been poorly understood. Recent studies profiling genome-wide DNA copy number alterations in CML and ALL have identified a near-obligate deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) in de novo BCR-ABL1 positive ALL, and at the progression of CML to lymphoid blast crisis, suggesting that perturbation of IKAROS activity is a key event in the pathogenesis of BCR-ABL1 lymphoid leukemia. To test this hypothesis, we have examined the effect of Ikaros haploinsufficiency in a retroviral bone marrow transplant model of murine BCR-ABL1 B-progenitor ALL. Unmanipulated marrow from either Ikzf1 wild type mice or mice heterozygous for an Ikzf1 null allele was transduced with MSCV bicistronic retrovirus expressing GFP and p185 BCR-ABL1 and transplanted into lethally irradiated C57BL/6 recipients. Recipients of MSCV-GFP-p185 BCR-ABL1-transduced Ikzf1^+/− marrow developed leukemia with markedly increased penetrance and reduced latency in comparison to recipients of wild-type marrow (46 vs. 122 d, P<0.0001). The resulting leukemias resulted in bone marrow replacement by lymphoblasts, pancytopenia, extramedullary infiltration, and frequent clinical and histologic central nervous system involvement. The leukemias were of pre-B immunophenotype and uniformly transplantable into sublethally irradiated secondary recipients. Importantly, detailed enumeration of lymphoid subsets in Ikzf^+/+ and ^+/− marrow did not demonstrate an expansion of lymphoid progenitors in Ikzf1^+/− marrow, suggesting that the observed increased penetrance of B-ALL in Ikzf1^+/− animals was not simply due to the expansion of targets of BCR-ABL1 transformation. Thus, Ikaros haploinsufficiency cooperates with BCR-ABL1 to induce an aggressive pre-B leukemia with clinical and pathologic features recapitulating human BCR-ABL1 ALL. These results support genomic analyses of human leukemia suggesting that IKAROS loss is important in the pathogenesis of this disease. Experiments evaluating the interaction of Ikzf1 loss with other targets of genomic alteration in BCR-ABL1 ALL (e.g. CDKN2A/B, PAX5), and the role of dominant negative isoforms of Ikaros in leukemogenesis will be of interest.