Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression

作者：Beer Philip A; Knapp David J H F; Miller Paul H; Kalman Nagarajan; Sloma Ivan; Heel Kathy; Babovic Sonja; Bulaeva Elizabeth; Rabu Gabrielle; Terry Jefferson; Druker Brian J; Loriaux Marc M; Loeb Keith R; Radich Jerald P; Erber Wendy N; Eaves Connie J^*

来源：Blood, 2015, 125(3): 504-515.

DOI：10.1182/blood-2014-06-581173

Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1 negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoform of IKAROS (IK6) in CP-CML patients' CD34(+) cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenograf-ted mice of primitive cells with an enhanced ability to differentiate into basophils. Expression of IK6 in CD34(+) CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients.

• 出版日期2015-1-15