The controversial role of the Hedgehog pathway in normal and malignant hematopoiesis.
The controversial role of the Hedgehog pathway in normal and malignant hematopoiesis.
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刺猬途径在正常和恶性造血中有争议的作用。
作者：
Hedgehog（Hh）是一种发育信号通路，其中Hh配体结合Patched（Ptch），这减轻了其对Smoothened（Smo）的抑制，允许Gli家族的转录因子易位到细胞核并激活Hh靶基因。Hh信号在造血中的作用是有争议的和不明确的。尽管一些组观察到自我更新缺陷，再铺板减少，二次小鼠移植效率降低，但其他组报告没有造血表型，这可能与Hh废除的时间有关。在恶性造血中，大多数注意力集中在Hh信号传导在慢性髓性白血病（CML）中的作用，许多人认为CML是一种具有组成性活性BCR-ABL酪氨酸激酶的干细胞疾病。尽管通过BCR-ABL抑制消除了大多数白血病细胞，但大多数患者仍保持PCR阳性，这表明假定的CML干细胞可能对激酶拮抗剂具有抗性。研究小组现在正在探索Hh通路作为支持CML干细胞存活的替代通路。在几种体外和体内模型中，Smo的敲低或抑制消除或延迟CML的出现。这些数据导致了使用BCR-ABL激酶和新型Smo抑制剂组合的临床试验。
Hedgehog (Hh) is a developmental signaling pathway in which Hh ligands bind Patched (Ptch), which relieves its inhibition of Smoothened (Smo), allowing the Gli family of transcription factors to translocate to the nucleus and activate Hh target genes. The role of Hh signaling in hematopoiesis is controversial and ill defined. Although some groups observed self-renewal defects with decreased replating and reduced efficiency of secondary murine transplants, other groups reported no hematopoietic phenotypes, which may be related to the timing of Hh abrogation. In malignant hematopoiesis, most attention has been focused on the role of Hh signaling in chronic myeloid leukemia (CML), considered by many to be a stem cell disorder that bears the constitutively active BCR-ABL tyrosine kinase. Despite the elimination of most leukemia cells through BCR-ABL inhibition, most patients remain PCR positive, suggesting that the putative CML stem cell may be resistant to kinase antagonism. Groups are now exploring the Hh pathway as an alternate pathway supporting CML stem cell survival. Knockdown or inhibition of Smo abrogates or delays the appearance of CML in several in vitro and in vivo models. These data have lead to clinical trials using BCR-ABL kinase and novel Smo inhibitors in combination.
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