Spred1 is highly expressed in normal hematopoietic stem cells (HSCs). Lack of Spred1 function has been associated with aberrant hematopoiesis and acute leukemias. In chronic myelogenous leukemia (CML), Spred1 is reduced in patients with accelerated phase (AP) or blast crisis (BC) CML, thereby suggesting that deficit of this protein may contribute to disease transformation. In fact, Spred1 knockout (KO) in SCLtTA/BCR-ABL CML mice either globally, or restricted to hematopoietic cells (i.e., HSCs) or to endothelial cells (ECs), led to transformation of chronic phase (CP) CML into AP/BC CML. Upon BCR-ABL induction, all three Spred1 KO CML models showed AP/BC features. However, compared with global Spred1 KO, the AP/BC phenotypes of HSC-Spred1 KO and EC-Spred1 KO CML models were attenuated, suggesting a concurrent contribution of Spred1 deficit in multiple compartments of the leukemic bone marrow niche to the CML transformation. Spred1 KO, regardless if occurred in HSCs or in ECs, increased miR-126 in LSKs (Lin⁻Sca-1⁺c-Kit⁺), a population enriched in leukemic stem cells (LSCs), resulting in expansion of LSCs, likely through hyperactivation of the MAPK/ERK pathway that augmented Bcl-2 expression and stability. This ultimately led to enhancement of Bcl-2-dependent oxidative phosphorylation that supported homeostasis, survival and activity of LSCs and drove AP/BC transformation.

Spred1 在正常造血干细胞 (HSC) 中高表达。 Spred1 功能缺乏与造血异常和急性白血病有关。在慢性粒细胞白血病 (CML) 中，加速期 (AP) 或急变期 (BC) CML 患者的 Spred1 减少，因此表明该蛋白的缺乏可能有助于疾病转化。事实上，SCLtTA/BCR-ABL CML 小鼠中的 Spred1 敲除 (KO) 要么是全局性的，要么仅限于造血细胞 (即 HSC) 或内皮细胞 (EC)，导致慢性期 (CP) CML 转化为 AP/ BC CML。 BCR-ABL 诱导后，所有三种 Spred1 KO CML 模型均显示出 AP/BC 特征。然而，与整体 Spred1 KO 相比，HSC-Spred1 KO 和 EC-Spred1 KO CML 模型的 AP/BC 表型减弱，表明白血病骨髓微环境多个区室的 Spred1 缺陷对 CML 转化同时起作用。 Spred1 KO，无论发生在 HSC 还是 EC，都会增加 LSK（Lin ⁻ Sca-1 ⁺ c-Kit ⁺ ）（富含白血病干细胞 (LSC) 的群体）中的 miR-126，从而导致 LSC 的扩增，可能是通过MAPK/ERK 通路的过度激活增强了 Bcl-2 的表达和稳定性。这最终导致 Bcl-2 依赖性氧化磷酸化的增强，支持 LSC 的稳态、存活和活性，并驱动 AP/BC 转化。