1014 – AGE-DEPENDENT STEMNESS PROGRAMS THAT DRIVE PEDIATRIC ACUTE MYELOID LEUKEMIA

IF 2.5 4区 医学 Q2 HEMATOLOGY
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引用次数: 0

Abstract

Pediatric acute myeloid leukemia is a genetically diverse malignancy with some mutations conveying particularly high risk for relapse and death. For example, NUP98-rearranged (NUP98r) AML occurs primarily in early to mid-childhood, and it carries an overall survival of only 10-30%. It is not clear why NUP98r AML occurs disproportionately in mid-childhood or how to more effectively treat it.

We used a combination of mouse and human models to identify self-renewal programs that sustain NUP98r AML and test whether they are engaged most efficiently during neonatal or juvenile stages of life, as might be expected based on peak age of presentation. We isolated a conserved leukemia stem cell (LSC) population. The LSC signature distinguishes NUP98r AML from other pediatric AML subtypes, and it includes new candidate targets for therapy.

Age greatly influences the capacity of pre-leukemic progenitors to self-renew, transform and give rise to LSCs. Specifically, we found that the fetal state confers an unanticipated layer of protection against NUP98r AML. NUP98::HOXA9 induction in fetal progenitors causes precocious erythroid differentiation. In contrast, NUP98::HOXA9 induction in postnatal progenitors hyperactivates self-renewal programs while preserving an otherwise normal hematopoietic differentiation trajectory. NUP98::HOXA9-expressing neonatal progenitors self-renew, form colonies and give rise to AML far more efficiently than fetal progenitors. The fetal state confers similar protection against KMT2A::MLLT1-driven AML, another high-risk subtype. Active fetal leukemia suppression may explain why fetal leukemias are exceedingly rare even when leukemogenic mutations arise before birth.

Interestingly, fetal protection does not extend to all pediatric AML oncoproteins. The infant AML driver, MNX1, causes marked expansion of fetal progenitors that dissipates almost entirely after birth. Thus, ontogeny has mutation-specific effects on self-renewal and leukemogenic potential.

1014 - 驱动小儿急性髓性白血病的年龄依赖性干细胞程序
小儿急性髓性白血病是一种基因多样化的恶性肿瘤,某些基因突变导致复发和死亡的风险特别高。例如,NUP98重组(NUP98r)急性髓细胞白血病主要发生在儿童早期至中期,其总生存率仅为10%-30%。我们结合使用了小鼠和人类模型,以确定维持 NUP98r AML 的自我更新程序,并测试这些程序是否在新生儿期或青少年期最有效地发挥作用,这可能是基于发病高峰年龄的预期。我们分离出一个保守的白血病干细胞(LSC)群体。年龄在很大程度上影响着白血病前祖细胞自我更新、转化和产生白血病干细胞的能力。具体而言,我们发现胎儿状态赋予了NUP98r急性髓细胞性白血病意想不到的保护层。在胎儿祖细胞中诱导 NUP98::HOXA9 会导致红细胞早熟分化。与此相反,NUP98::HOXA9 在出生后祖细胞中的诱导会过度激活自我更新程序,同时保留正常的造血分化轨迹。表达NUP98::HOXA9的新生儿祖细胞自我更新、形成集落和产生急性髓细胞的效率远远高于胎儿祖细胞。胎儿状态对另一种高风险亚型--KMT2A::MLLT1驱动的急性髓细胞白血病也有类似的保护作用。胎儿对白血病的主动抑制可能解释了为什么即使在出生前出现致白血病突变,胎儿白血病也极为罕见。婴儿急性髓细胞性白血病驱动基因 MNX1 会导致胎儿祖细胞明显增殖,而这种增殖在出生后几乎完全消失。因此,本体发生对自我更新和致白血病潜能具有突变特异性影响。
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来源期刊
Experimental hematology
Experimental hematology 医学-血液学
CiteScore
5.30
自引率
0.00%
发文量
84
审稿时长
58 days
期刊介绍: Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.
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