Abstract：
UNASSIGNED: SETBP1 mutations are found in various clonal myeloid disorders. However, it is unclear whether they can initiate leukemia, because SETBP1 mutations typically appear as later events during oncogenesis. To answer this question, we generated a mouse model expressing mutated SETBP1 in hematopoietic tissue: this model showed profound alterations in the differentiation program of hematopoietic progenitors and developed a myeloid neoplasm with megakaryocytic dysplasia, splenomegaly, and bone marrow fibrosis, prompting us to investigate SETBP1 mutations in a cohort of 36 triple-negative primary myelofibrosis (TN-PMF) cases. We identified 2 distinct subgroups, one carrying SETBP1 mutations and the other completely devoid of somatic variants. Clinically, a striking difference in disease aggressiveness was noted, with patients with SETBP1 mutation showing a much worse clinical course. In contrast to myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in 3 patients with TN-PMF from our cohort revealed SETBP1 to be a very early event, suggesting that the phenotype of the different SETBP1+ disorders may be shaped by the opposite hierarchy of the same clonal SETBP1 variants.
摘要：
SETBP1突变存在于各种克隆性髓样疾病中。然而,目前还不清楚他们是否可以引发白血病，SETBP1突变通常在肿瘤发生过程中作为后期事件出现。为了回答这个问题,我们建立了一个在造血组织中表达突变SETBP1的小鼠模型：该模型显示了造血祖细胞分化程序的深刻改变，并发展出具有巨核细胞发育不良的髓系肿瘤，脾肿大,和骨髓纤维化，提示我们在36例三阴性原发性骨髓纤维化（TN-PMF）病例队列中研究SETBP1突变。我们确定了两个不同的亚组，一个携带SETBP1突变，另一个完全没有体细胞变异。临床上,注意到疾病侵袭性的显著差异，SETBP1突变的患者表现出更差的临床病程。与骨髓增生异常/骨髓增生性肿瘤相反，SETBP1突变主要是作为晚期克隆事件发现的，来自我们队列的三名TN-PMF患者的单细胞克隆层次重建显示SETBP1是非常早期的事件，表明不同SETBP1+疾病的表型可能由相同克隆SETBP1变体的相反层次形成。
