CRLF2 signaling in B-cell acute lymphoblastic leukemia

描述（由申请人提供）：拟议研究的主要目的是确定过度表达细胞因子受体CRLF2的前体b细胞急性淋巴细胞白血病（b - all）是否依赖CRLF2信号存活。通过功能性筛查，我们最近发现CRLF2在大约15%缺乏常见染色体重排的成人和高危儿童B-ALL以及60%患有唐氏综合征的儿童B-ALL中是促生长信号的驱动因素。成人crlf2过表达B-ALL患者的预后尤其差，在我们的研究中，4年总生存率为0%。CRLF2过表达一致是由于CRLF2位点的基因组重排，通过间质缺失或易位。根据CRLF2本身或受体相关激酶JAK2中存在或不存在体细胞突变，过表达CRLF2的B- all可分为三类。我们的中心假设是CRLF2过表达的b - all依赖于CRLF2信号的生存。如果是这样，这些B-ALL可以靶向小分子激酶抑制剂，类似于对表达BCR/ABL融合激酶的B-ALL使用激酶抑制剂伊马替尼。对于Specific Aim #1，我们将确定突变体JAK2在CRLF2信号传导中的作用。这些研究将利用淋巴样细胞系和纯化蛋白确定CRLF2和JAK2之间的物理关系，确定这种关系是否依赖于JAK2突变，并阐明CRLF2对JAK2活性的重要区域。在Aim #2中，我们将定义CRLF2信号传导的基本成分，包括CRLF2受体复合物的成员、受体配体和下游激酶。在Aim #3中，我们将在体内定义B-ALL对CRLF2信号的依赖性。这些研究将使用原代人类异种移植物和B-ALL细胞系来建立目标#1和#2的发现，首先通过表征对CRLF2信号特定成分的体内依赖性，然后通过将这种依赖性与对激酶抑制剂的反应相关联。治疗性JAK抑制剂目前正处于治疗骨髓增殖性疾病的临床试验中，这为将CRLF2的发现迅速转化为B-ALL患者的定向治疗创造了一个令人兴奋的机会。最后，原发性异种移植物将是我们长期努力确定和克服这种疾病治疗耐药的生物学决定因素的宝贵平台。

DESCRIPTION (provided by applicant): The primary goal of the proposed studies is to establish whether precursor B-cell acute lymphoblastic leukemias (B-ALLs) that overexpress the cytokine receptor CRLF2 are dependent on CRLF2 signaling for survival. Using a functional screen, we recently identified CRLF2 as a driver of pro-growth signaling in approximately 15% of adult and high-risk pediatric B-ALL that lack common chromosomal rearrangements, and 60% of B-ALL in children with Down syndrome. Outcomes among adults with CRLF2-overexpressing B-ALL is particularly poor, with 0% 4-year overall survival in our series. CRLF2 overexpression uniformly results from genomic rearrangement of the CRLF2 locus, either through an interstitial deletion or a translocation. B- ALLs that overexpress CRLF2 fall into one of three categories, based on the presence or absence of somatic mutations within either CRLF2 itself or the receptor-associated kinase JAK2. Our central hypothesis is that B-ALLs with CRLF2 overexpression are dependent on CRLF2 signaling for survival. If so, these B-ALLs could be targeted with small-molecule kinase inhibitors, akin to the use of the kinase inhibitor imatinib for B-ALL that express the BCR/ABL fusion kinase. For Specific Aim #1, we will determine the role of mutant JAK2 in CRLF2 signaling. These studies will define the physical relationship between CRLF2 and JAK2 using lymphoid cell lines and purified proteins, determine whether that relationship depends on JAK2 mutation and clarify the essential regions of CRLF2 for JAK2 activity. In Aim #2, we will define the essential components of CRLF2 signaling, including members of the CRLF2 receptor complex, the receptor ligand, and downstream kinases. In Aim #3, we will define the dependence of B-ALL on CRLF2 signaling in vivo. These studies will use primary human xenografts and B-ALL cell lines to build on the findings from Aims #1 and #2, first by characterizing in vivo dependence on specific components of CRLF2 signaling, and then by correlating that dependence with the response to kinase inhibitors. The availability of therapeutic JAK inhibitors, which are now in clinical trials for the treatment of myeloproliferative disorders, has created an exciting opportunity to rapidly translate the discovery of CRLF2 into a directed therapy for patients with B-ALL. Finally, the primary xenografts will be an invaluable platform for our long-term efforts to define and overcome the biologic determinants of therapeutic resistance in this disease. PUBLIC HEALTH RELEVANCE: We recently identified a new cancer protein, CRLF2, which confers a dismal prognosis in some patients with B-cell acute lymphoblastic leukemia (B-ALL). The two goals of our studies are: 1) to determine the mechanisms that CRLF2 uses to drive B-ALL growth and survival, and 2) to develop drugs that target CRLF2 signaling for testing in patients with B-ALL.