CRLF2 signaling in B-cell acute lymphoblastic leukemia

描述(申请人提供)：拟议研究的主要目标是确定过度表达细胞因子受体CRLF2的前驱B细胞急性淋巴细胞性白血病(B-ALL)是否依赖CRLF2信号生存。利用功能筛查，我们最近在大约15%的成人和高危儿童B-ALL中发现CRLF2是促生长信号的驱动因素-所有B-ALL缺乏常见的染色体重排，而60%的B-ALL在唐氏综合征儿童中。CRLF2过度表达的成人B-ALL的预后特别差，在我们的系列中，4年总存活率为0%。CRLF2的过度表达是CRLF2基因座基因组重排的统一结果，通过间质缺失或易位。根据CRLF2本身或受体相关激酶JAK2内是否存在体细胞突变，过度表达CRLF2的B细胞可分为三种类型之一。我们的中心假设是CRLF2过表达的B-ALL的生存依赖于CRLF2信号。如果是这样的话，这些B-ALL可以被小分子激酶抑制剂作为靶点，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。对于特定的目标1，我们将确定突变的JAK2在CRLF2信号中的作用。这些研究将使用淋巴样细胞系和纯化的蛋白质来确定CRLF2和JAK2之间的物理关系，确定这种关系是否依赖于JAK2突变，并澄清CRLF2对JAK2活性的必要区域。在目标2中，我们将定义CRLF2信号的基本组件，包括CRLF2受体复合体的成员、受体配体和下游激酶。在目标3中，我们将定义B-ALL对体内CRLF2信号的依赖性。这些研究将使用原代人类异种移植和B-ALL细胞系，以AIMS#1和#2的发现为基础，首先通过在体内表征对CRLF2信号的特定成分的依赖性，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生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，初级异种移植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。 公共卫生相关性：我们最近发现了一种新的癌症蛋白CRLF2，它使一些B细胞急性淋巴细胞白血病(B-ALL)患者的预后变得黯淡。我们研究的两个目标是：1)确定CRLF2用来驱动B-ALL生长和存活的机制，2)开发针对CRLF2信号的药物，用于B-ALL患者的测试。

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.