Take (STAT)5: jazzing up T-cell leukemia

In this issue of Blood, Kiel et al identify novel and high-frequency gain-of-function mutations involving genes of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway in T-cell prolymphocytic leukemia (T-PLL), paving the way for new targeted therapies.¹ 

Although significant strides are being made in the molecular classification of mature T-cell lymphomas and leukemias (MTCLL),²  the genetic steps that lead to the neoplastic transformation of mature T cells and drive the emergence, progression, and clinical outcome of these malignancies remain unsolved. Some glimpse of the initial genomic and signaling events supporting the uncontrolled, clonal outgrowth of postthymic T-cell subsets in vivo is now being gained through the window of newly described murine models of MTCLL. Some of these models highlight the role of T-cell receptor (TCR)-activated pathways such as TCL1/AKT and SYK/ITK (reviewed by Warner et al³ ), while others reveal the importance of epigenetic mechanisms in T-cell transformation, as shown by interleukin-15 transgenic mice.⁴  The relative importance of genetic vs epigenetic events in the neoplastic transformation of human mature T-cells is an open question with significant clinical implications, and a very preliminary look at ongoing next-generation sequencing studies, including the one from Kiel et al, suggests that the rate of somatic mutations and the frequency of epigenetic aberrations may differ significantly across the spectrum of human MTCLL. As Kiel et al demonstrate, mapping the genetic landscape of MTCLL is already providing new opportunities for understanding the common pathogenesis and targeting the specific molecular drivers that are at play in these cancers.

Among the key mediators of intracellular signaling in response to regulatory cytokines during blood cell development and the immune responses, the members of the JAK/STAT pathway have long been known to play a central role.⁵  Not surprisingly, somatic mutations of JAK/STAT genes and constitutive activation of JAK and STAT proteins have been observed in myeloid and lymphoid neoplasms⁶  and are now surfacing as recurrent genetic hits in different types of MTCLL.^7-9  However, our knowledge of the specific role that the JAK/STAT family members play in T-cell oncogenesis remains limited. In this respect, the study of Kiel et al significantly expands our understanding of the impact of this key regulatory pathway in MTCLL by revealing that STAT5B, in addition to the previously described JAK1 and JAK3,^7,8  is the most common target of somatic mutations in T-PLL.

T-PLL is a rare and highly chemoresistant leukemic neoplasm of mature CD3⁺, TCRαβ, CD4⁺ T cells, affecting older adults (median age, 61 years).¹⁰  Prior to the introduction of alemtuzumab (Campath-1H), complete responses (CRs) were rare and median survival was only 7 months. With alemtuzumab, most patients achieve a CR, but in the absence of an allogeneic hematopoietic stem cell transplant, relapses are the rule and median survival is still <2 years. The treatment landscape in T-PLL remains barren, and new discoveries are desperately needed.

In their landmark report, Kiel et al have provided, for the first time, a comprehensive survey of somatic mutations in a large sample (N = 50) of clinically well-characterized T-PLL. The median survival of 27.1 months indicates that the cohort is representative of the expected natural history of T-PLL, and the fact that the majority of the samples (75.5%) were collected prior to initiation of therapy supports the conclusion that the observed mutations are credible candidates as disease-initiating or at least disease-driving events. Initially focusing on 4 index cases, Kiel et al first performed a careful confirmatory survey of known genetic aberrations in T-PLL, focusing on the TCL1A, TCL1B, MTCP1, and ATM genes. Having found one or more of these aberrations in all samples, with an array of methodologies that included whole-genome and whole-exome sequencing, they then analyzed mutations at loci not previously known to be involved in T-PLL pathogenesis. Among them, Kiel et al found a staggeringly high rate of mutations affecting STAT5B (36%), JAK3 (30%), and JAK1 (8%), together with previously never reported mutations of the IL-2 receptor (IL-2R) γ (1 patient). Having confirmed the oncogenic relevance of these mutations in canonical in vitro assays, Kiel et al conclude that disruption of the IL-2R-JAK1/3-STAT5 signaling axis is a dominant feature of T-PLL biology and identify this pathway as a high-priority target for new therapies.

That’s where things become really interesting from a clinical standpoint. The known convergence of IL-2R signaling on STAT5B, the observed prevalence of STAT5B mutations, and the coexistence of JAK1, JAK3, and STAT5B mutations in a small subset of cases predict that targeting STAT5B may have the best chance of inhibiting growth and survival signals in T-PLL cells. To confirm that, Kiel et al show that pimozide, an oral antipsychotic drug approved in the United States for the treatment of Tourette syndrome and a known STAT5 inhibitor, decreases cell proliferation and induces apoptosis in the T-cell line Hut78 and in primary tumor cells harboring the activating mutations, offering proof-of-principle data that identify STAT5 as a key target of therapy in T-PLL. The question now is how best to target STAT5 in the clinic. Although the in vitro data are highly encouraging, the safety profile of neuroleptics makes it unlikely that pimozide will become a viable anticancer drug, and efforts should now be devoted to the identification and study of new STAT5 inhibitors. Nonetheless, Kiel et al give us for the first time a welcome insight on what may turn out to be the Achilles’ heel of T-PLL and point the way toward the development of much-needed new treatments for this ghastly disease.