We previously defined a high-risk subset of B-cell acute lymphoblastic leukemia (B-ALL) that harbor either P2RY8-CRLF2 deletions or CRLF2-IGH@ translocations that result in CRLF2 overexpression. The long-term goal of our R01 project is to improve the outcomes of patients with CRLF2-rearranged B-ALL by defining essential signaling downstream of CRLF2 and developing pre-clinical evidence for inhibitors of that signaling. Over the first 5 years of support, we have built on the discovery of CRLF2 rearrangements to define aspects of molecular epidemiology and signaling associated with these alterations, determine the mechanism of chromosomal breakage that results in CRLF2-IGH@ translocations, demonstrate that HSP90 inhibitors, BRD4 inhibitors and type II JAK2 inhibitors have activity against CRLF2-rearranged B-ALLs in vivo, and develop both transgenic and patient-derived xenograft models of CRLF2-dependent B-ALL. These studies have resolved several issues relevant to CRLF2 biology but also generated central questions about the difference between the two types of CRLF2 rearrangements and the most effective strategy for targeting CRLF2 signaling. CRLF2 heterodimerizes with the IL7R? subunit and signals through JAK2 (bound to CRLF2) and JAK1 (bound to IL7R?). Despite the requirement for JAK2 signaling downstream of CRLF2, type I JAK2 inhibitors induce JAK2 hyper-phosphorylation and are largely ineffective in CRLF2-rearranged human B-ALL cells in vitro and in vivo. JAK2 hyper-phosphorylation may depend on JAK1 (or other JAK family members) acting in trans, as previously demonstrated in cells dependent on JAK2 V617F. JAK2 phosphorylation is completely abrogated by type II inhibitors, which stabilize JAK2 in an inactive conformation. Our published studies now demonstrate that the type II JAK2 inhibitor CHZ868 suppresses JAK2 signaling in human CRLF2-rearranged B-ALL cells and is highly active both in vitro and in vivo.
In Aim 1, we will define the mechanisms of resistance to both type I and type II JAK2 inhibitors in CRLF2-dependent B-ALLs. Our central hypothesis is that CRLF2-rearranged B- ALLs with resistance to type I or type II inhibitors remain addicted to CRLF2/JAK2 signaling. Approximately 60% of B-ALL in children with Down syndrome harbor P2RY8-CRLF2 deletions but CRLF2-IGH@ translocations are extremely rare in these children.
In Aim 2, we will determine how P2RY8-CRLF2 deletions affect B cell leukemogenesis in the presence or absence of trisomy 21. We hypothesize that deletion of one or more loci between P2RY8 and CRLF2 contributes to B-ALL in the context of trisomy 21. These studies will provide essential insights into two outstanding questions relevant to CRLF2-dependent B-ALL, while utilizing our novel translational models to further the targeted treatment of patients with these high-risk leukemias.

Public Health Relevance

The outcomes for patients with B-cell acute lymphoblastic leukemia (B-ALL) that harbor CRLF2 rearrangements remain poor. The goal of our R01 program is to characterize signaling downstream of CRLF2 and identify new approaches to target that signaling. We will utilize a panel of innovative leukemia models to determine the effects from CRLF2 rearrangement and the mechanisms of resistance to JAK2 inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151898-08
Application #
9439690
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Jhappan, Chamelli
Project Start
2010-07-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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Day, Tovah A; Layer, Jacob V; Cleary, J Patrick et al. (2017) PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA. Nat Commun 8:15110
Wu, Shuo-Chieh; Li, Loretta S; Kopp, Nadja et al. (2015) Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia. Cancer Cell 28:29-41
Huang, Tai-Chung; Cutler, Jevon; Bharne, Shubhada et al. (2015) Integrated analysis of CRLF2 signaling in acute lymphoblastic leukemia identifies Polo-like kinase 1 as a potential therapeutic target. Leuk Lymphoma 56:1524-7
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Ott, Christopher J; Kopp, Nadja; Bird, Liat et al. (2012) BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood 120:2843-52
Weigert, Oliver; Lane, Andrew A; Bird, Liat et al. (2012) Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med 209:259-73

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