Adult T-cell leukemia/lymphoma (ATLL) like most T-cell neoplasms is in dire need of novel therapeutic advances. Typical of T-cell lymphomas, ATLL presents with multi-organ infiltration and extreme treatment resistance. Unfortunately, most ATLL patients die within one year of diagnosis and current drug regimens do not extend this dismal prognosis. ATLL is initiated by infection from a complex retrovirus, Human T- Lymphotropic Virus type I (HTLV-1). After initial infection, viral proteins expressed by HTLV-1, notably tax, transcriptionally activate expression of IL2 and IL2R genes resulting in lymphoproliferation by autocrine signaling. ATLL manifests after long latency but the tax gene is usually deleted or silenced by methylation. Thus, in late stage disease, the viral stimulus of IL-2 signaling is gone but leukemic cells remain hyper- responsive to cytokines that utilize the IL2R common gamma chain (IL2RG), suggesting a role for host factors in tumor progression. In support of this idea, we recently discovered gain of function mutations in JAK3 in 11% of ATLL patients and also noted frequent overexpression and kinase activation. JAK3 is a non-receptor tyrosine kinase that binds with IL2RG to transduce signals from multiple cytokine receptors (IL2R, IL4R, IL7R, IL9R, IL15R, and IL21R) upon ligand binding. Importantly, cell lines dependent upon mutant JAK3 are sensitive to tofacitinib, a specific JAK3 inhibitor currently being tested in patients with autoimmune diseases such as rheumatoid arthritis and psoriasis. Tofacitinib has been reported to have efficacy in phase III trials of rheumatoid arthritis and is the first such compound nearing approval.
In Aim 1, we will investigate the in vivo role of mutant JAK3 expression using bone marrow transduction and transplantation experiments. We will test the cooperativity of mutant JAK3 with Cdkn2a-/- and the viral tax oncogene.
In Aim 2, we will treat JAK3- induced lymphomas with tofacitinib, a specific JAK3 inhibitor.
In Aim 3, we will explore how negative regulators of the JAK3 pathway may be involved in ATLL pathogenesis.
Our aims are well-timed and can have a significant impact on a disease that is universally fatal upon diagnosis and advance our understanding of JAK3's role in T-cell neoplasia.
T-cell non-Hodgkin lymphomas and leukemias are highly resistant to standard treatment options. These aggressive cancers develop in males more often than females and affect patients at 60 years of age. This is the exact demographic that comprises the Veteran population. Unfortunately, most Veterans with T-cell lymphomas will succumb to their disease so there is a desperate need for novel therapeutic approaches. Our laboratory has been studying a unique example of T-cell non-Hodgkin lymphoma called Adult T-cell leukemia/lymphoma (ATLL) where we discovered a mutation in an enzyme, JAK3. Most interestingly, there are drugs being developed that block the normal function of JAK3 that could be potentially applied in T-cell lymphomas that use JAK3 for their growth. In this grant, we propose experiments and models to understand how JAK3 induces lymphomas. The studies will generate data that will be needed to incorporate JAK3 inhibitors into the treatment of these deadly cancers.
| Greenplate, Allison; Wang, Kai; Tripathi, Rati M et al. (2018) Genomic Profiling of T-Cell Neoplasms Reveals Frequent JAK1 and JAK3 Mutations With Clonal Evasion From Targeted Therapies. JCO Precis Oncol 2018: |
| Efimenko, Evgeni; Davé, Utpal P; Lebedeva, Irina V et al. (2017) PI3K?/? and NOTCH1 Cross-Regulate Pathways That Define the T-cell Acute Lymphoblastic Leukemia Disease Signature. Mol Cancer Ther 16:2069-2082 |
| Layer, Justin H; Alford, Catherine E; McDonald, W Hayes et al. (2016) LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding. Mol Cell Biol 36:488-506 |
| Goodings, Charnise; Smith, Elizabeth; Mathias, Elizabeth et al. (2015) Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation. Stem Cells 33:2628-41 |
| McGirt, Laura Y; Jia, Peilin; Baerenwald, Devin A et al. (2015) Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood 126:508-19 |
| Goodings, Charnise; Tripathi, Rati; Cleveland, Susan M et al. (2015) Enforced expression of E47 has differential effects on Lmo2-induced T-cell leukemias. Leuk Res 39:100-9 |
| Cleveland, Susan M; Goodings, Charnise; Tripathi, Rati M et al. (2014) LMO2 induces T-cell leukemia with epigenetic deregulation of CD4. Exp Hematol 42:581-93.e5 |
| Smith, Stephen; Tripathi, Rati; Goodings, Charnise et al. (2014) LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways. PLoS One 9:e85883 |
| Cleveland, Susan M; Smith, Stephen; Tripathi, Rati et al. (2013) Lmo2 induces hematopoietic stem cell-like features in T-cell progenitor cells prior to leukemia. Stem Cells 31:882-94 |
| Yan, Ling; Womack, Bethany; Wotton, David et al. (2013) Tgif1 regulates quiescence and self-renewal of hematopoietic stem cells. Mol Cell Biol 33:4824-33 |
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