Abstract 1488: Role of niche requirements in transient leukemia of Down syndrome

Abstract

Abstract Background. Children with Down syndrome (DS; constitutional trisomy 21) display an estimated 150-fold increased incidence of acute myeloid leukemia (AML/AMkL). Leukemic blasts are detectable in the peripheral blood of approximately 10% of newborns with DS. This pre-leukemic disorder, known as Transient Leukemia (TL) or Transient Myeloproliferative Disorder (TMD), predominantly undergoes spontaneous resolution, although 20% of cases go on to develop AML later in life. Available data suggest that TL is a disorder of fetal hematopoiesis, triggered by somatic mutations of the hematopoietic transcription factor GATA1. We hypothesize that the transition from fetal to post-natal hematopoiesis results in the elimination of TL blasts in the majority of cases, and that progression events acquired during the first three years of life account for the transformation of Down syndrome TL to AML. Methods and Results. During embryonic development, the fetal liver (FL) constitutes the primary site of hematopoiesis. Data from our xenotransplant model suggest that the post-natal bone marrow (BM) environment provides insufficient or inappropriate cues for the survival, proliferation and dissemination of TL blasts. To identify the unique combination of signals provided by the FL but not the post-natal BM, we reconstructed both hematopoietic niches in vitro by culturing primary human TL cells on murine stromal cell lines derived from either FL (Aft024) or adult BM (MS-5). We found that TL cells underwent a striking >80-fold expansion in total cell number when cultured on FL-derived stromal cells for 2 weeks. In contrast, BM-derived MS-5 stromal cells supported only a moderate 8-fold expansion of TL cells, simultaneously allowing for progressive induction of apoptosis, and inducing increased myeloid differentiation. The superior ability of fetal-derived stromal cells compared to those derived from bone marrow to support TL cells was confirmed under hypoxic culture conditions, in keeping with their fetal origin. Comparative gene expression analysis successfully identified both soluble and membrane-bound components of the fetal hematopoietic niche (modeled by Aft024), such as BMPs and mediators of cell adhesion, as candidate regulators of TL cell growth. Conclusions. We have developed an ex vivo culture system which allows the expansion of primary DS-TL blast cells. We demonstrate that survival/proliferative signals are preferentially provided by the fetal liver vs. adult bone marrow environment, consistent with a fetal origin of TL blasts. Our current focus is on the identification and functional validation of signaling pathways that are essential for TL blast survival and whose interruption in this pre-leukemic disorder may lead to prevention of subsequent AML in children with Down syndrome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1488. doi:1538-7445.AM2012-1488