Lymphopoietic niche editing by B-lineage leukemic cells and its implications for B cell progenitor and leukemic cell growth

总结：B细胞急性淋巴细胞白血病（B-ALL）目前采用化疗治疗， 相对较高的成功率。然而，化疗会导致长期后遗症，特别是在儿科 人口。在老年人中，化疗往往不足以消除B-ALL， 没有其他治疗方法因此，对新靶点和治疗策略的追求必须继续下去， 面对特别敏感的患者群体的需求。B-ALL最常见的形式是 费城染色体preB ALL。在过去的两年里，我们一直在研究 发育中的B淋巴细胞和骨髓中罕见但生理上关键的基质细胞群 称为间充质祖细胞（MPC），其产生白细胞介素-7（IL-7）。在最近发表的一项研究中， 我们描述了proB和MPC之间以及preB细胞和MPC之间形成的两个细胞回路， 调节B细胞发育的早期阶段。这些发现使我们有了一个意想不到的发现， 白血病preB细胞和费城染色体preB-ALL细胞与MPC物理相互作用， 骨髓中MPC的IL-7产生。在最近的未发表的研究中，我们发现了一种新的光敏素， 在白血病前和白血病前B细胞上表达的LTa1b2配体和光敏素β受体（LTbR） 作为控制MPC产生IL-7的分子机制。重要的是，转- 非白血病B系细胞的发育导致前B-ALL的加速生长，这表明 两种细胞类型竞争限制因子。值得注意的是，我们的初步研究表明， 细胞和非白血病B细胞祖细胞高度依赖于细胞合成代谢营养谷氨酰胺 增殖/生长。结合起来，我们未发表的发现使我们得出了这项资助的主要假设：1- 治疗靶向MPC中的LTbR信号传导改变了骨髓微环境并减少了前B细胞亚群。 前B-ALL细胞与非白血病的"正常B祖细胞"竞争限制ALL细胞生长， 骨髓微环境中的谷氨酰胺含量。这些假设将在两个相关的测试 独立的目标。在目标1中，我们将测试骨髓MPCs中LTbR信号传导在减缓细胞凋亡中的影响。 抑制体内前B-ALL的生长。我们将使用转基因小鼠模型与 LTbR阻断试剂，以确定通过改变IL-7产生是否使preB-ALL生长降低到一定程度 其允许T细胞介导的同种异体前B-ALL的体内清除。在目标2中，我们将探讨 谷氨酰胺类似物6-重氮-5-氧代-L-正亮氨酸的治疗潜力，一种有效的谷氨酰胺拮抗剂 代谢，在体内防止preB-ALL细胞增殖。这些目标的成功可能会产生重大影响 B-ALL的治疗，并为其他血液癌症的治疗开辟新的治疗策略。

Summary: B cell acute lymphoblastic leukemias (B-ALL) are currently treated with chemotherapy with a relatively high success rate. However, chemotherapy causes long-lasting sequellae particularly in pediatric populations. In the elderly, chemotherapy is often insufficient for eliminating B-ALL, leaving these patients without therapeutic alternatives. Therefore, the pursuit for new targets and therapeutic strategies must go on to face the needs of particularly sensitive populations of patients. The most prevalent form of B-ALL is the Philadelphia chromosome preB ALL. Over the past 2 years we have been studying the crosstalk between developing B lymphocytes and a rare but physiologically critical population of stromal cells in the bone marrow known as mesenchymal progenitor cells (MPCs) that produce Interleukin-7 (IL-7). In a recently published study we described two cell circuits formed between proB and MPCs, and between preB cells and MPCs, that regulate early stages of B cell development. These findings led us to an unexpected discovery that pre- leukemic preB cells and Philadelphia chromosome preB-ALL cells physically interact with MPCs and turn-off IL-7 production by MPCs in bone marrow. In recent and unpublished studies we identified the lymphotoxin LTa1b2 ligand expressed on pre-leukemic and leukemic preB cells and the lymphotoxin beta receptor (LTbR) expressed on MPCs as the molecular mechanism that controls IL-7 production by MPCs. Importantly, turning- off the development of non-leukemic B-lineage cells results in accelerated growth of preB-ALLs, suggesting that both cell types compete for limiting factor(s). Remarkably, our preliminary studies revealed that preB-ALL cells and non-leukemic B cell progenitors are highly dependent on the anabolic nutrient Glutamine for cell proliferation/growth. Combined, our unpublished findings led us to the main hypotheses of this grant: 1- that therapeutic targeting of LTbR signaling in MPCs alters the bone marrow microenvironment and reduces preB- ALL cell growth; and 2- that preB-ALL cells compete with non-leukemic “normal B cell progenitors” for limiting amounts of Glutamine in the bone marrow microenvironment. These hypotheses will be tested in two related but independent aims. In aim 1, we will test the impact of LTbR signaling in bone marrow MPCs in slowing down the growth of preB-ALLs in vivo. We will use a combination of genetically modified mouse models with LTbR blocking reagents to determine if by altering IL-7 production preB-ALL growth is reduced to an extent that allows for T cell-mediated clearance of allogeneic preB-ALLs in vivo. In Aim 2, we will explore the therapeutic potential of the Glutamine analog 6-Diazo-5-oxo-L-norleucine, a potent antagonist of Glutamine metabolism, in preventing preB-ALL cell proliferation in vivo. Success in these aims may have a major impact on the treatment of B-ALL and open new therapeutic strategies for the treatment of other blood cancers.