The long-term goal of this project is to develop novel targeted therapies for T-cell acute lymphoblastic leukemia (T-ALL). T-ALL is an aggressive hematologic malignancy that comprises 15% of pediatric ALL and 25% of adult-ALL. Current treatment consists of intense chemotherapy that is associated with acute and chronic life-threatening or debilitating toxicities. Five-year event-free survival is 70-75% for children, 30-40% for adults under 60, and less than 10% for adults over age 60. The prognosis after relapse is dismal, with 3 year event-free survival of only 10-15%. There is compelling evidence that increased MYC activity is central to the pathogenesis of most cases of T-ALL. Although MYC is a potent oncogene, it has an Achilles heel. In addition to providing a proliferative signal, MYC strongly induces apoptosis, in part, through an ARF/MDM2/TP53 pathway. Indeed, without additional mutations/signals which inactivate apoptosis, increased MYC expression is not sufficient to induce leukemia/lymphoma. In T-ALL, this second signal is likely homozygous inactivating mutations of CDKN2A encoding p14 (ARF), which are present in ~80% of T-ALL. Together, these data support the hypothesis that agents that target MYC-associated survival pathways will be selectively toxic to T-ALL cells. CXCR4 is by far the most highly expressed chemokine receptor expressed on T-ALL cells, and there is evidence that CXCL12, through interaction with CXCR4, provides a key survival signal for T-ALL cells. Thus, we hypothesize that CXCR4 blockade may have therapeutic activity in T-ALL. Consistent with this hypothesis, our preliminary and published preclinical data show that T-ALL cells are exquisitely sensitive to CXCR4 inhibition. The following specific aims are proposed to test these hypotheses.
Aim 1. To test the combination of BL-8040 and nelarabine in adults with relapsed/refractory T- ALL/lymphoblastic lymphoma.
Aim 2. To develop novel therapeutic strategies that target the dependence of T-ALL on MYC-signaling.

Public Health Relevance

This project will explore the hypothesis that T-cell acute lymphoblastic leukemia (T-ALL) will be sensitive to drugs that interfere with MYC-survival signaling. This project includes a clinical trial of a novel CXCR4 antagonist (BL-8040) in combination with chemotherapy to treat patients with relapsed/refractory T-ALL.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Washington University
Saint Louis
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Duncavage, Eric J; Jacoby, Meagan A; Chang, Gue Su et al. (2018) Mutation Clearance after Transplantation for Myelodysplastic Syndrome. N Engl J Med 379:1028-1041
Khoury, Hanna Jean; Langston, Amelia A; Kota, Vamsi K et al. (2018) Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Bone Marrow Transplant 53:826-831
Schroeder, Mark A; Choi, Jaebok; Staser, Karl et al. (2018) The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia. Biol Blood Marrow Transplant 24:1125-1134
Perry, Justin S A; Russler-Germain, Emilie V; Zhou, You W et al. (2018) CD36 Mediates Cell-Surface Antigens to Promote Thymic Development of the Regulatory T Cell Receptor Repertoire and Allo-tolerance. Immunity 48:923-936.e4
Wong, Terrence N; Miller, Christopher A; Jotte, Matthew R M et al. (2018) Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat Commun 9:455
Christopher, Matthew J; Petti, Allegra A; Rettig, Michael P et al. (2018) Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N Engl J Med 379:2330-2341
Trissal, Maria C; Wong, Terrence N; Yao, Juo-Chin et al. (2018) MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis. Cancer Res 78:3510-3521
Jacoby, Meagan A; Duncavage, Eric J; Chang, Gue Su et al. (2018) Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant. JCI Insight 3:
Monlish, Darlene A; Bhatt, Sima T; Duncavage, Eric J et al. (2018) Loss of Toll-like receptor 2 results in accelerated leukemogenesis in the NUP98-HOXD13 mouse model of MDS. Blood 131:1032-1035
Choi, Jaebok; Cooper, Matthew L; Staser, Karl et al. (2018) Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia 32:2483-2494

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