#DYSMANTLE KAPPA CHECKPOINT DRIVER#

In low risk MDS, apoptosis plays a key role through T-cell inhibition.

(8) MDS transitions into acute myeloid leukemia (AML). (7) PD-L1 allows the MDS cells to escape immune surveillance by T-cell suppression.

(6) While continued inflammation leads to more apoptosis of hematopoietic stem cells (HSC) and cytopenias worsen, TNF-a and INF-Y start inducing PDL-1 expression on MDS clonal cells. (5) MSC also produce proinflammatory cytokines. (4) MSC in normal hematopoiesis suppress T-cell activation, a process that is aberrant in MDS. (3) This results in apoptosis in hematopoietic stem cells (HSC) resulting in cytopenias but also keep MDS cells (M) from proliferating. (2) CD-8+ T-cells produce cytokines like TNF-a and INF-Y. (1) Malignant MDS cells (M) induce clonal expansion of CD8+ T-cells (T). Low risk MDS patients remain stable for years with a 4-year survival rate of 80%, whereas high risk MDS is associated with poor outcomes and rapid progression to leukemia with a median survival of less than a year. Patients are risk stratified using several scores including the International Prognostic Scoring System (IPSS), revised IPSS, and the MD Anderson Cancer Center scores.

#DYSMANTLE KAPPA CHECKPOINT DRIVER#

A large number of somatic driver mutations in splicing factors and other epigenetic regulators are thought to have diagnostic and prognostic implications, with the exception of del(5q) and SF3B1 which are mentioned in the classification ( Table 1). According to the World Health Organization (WHO) classification, diagnosis of MDS is still based mostly on histologic and cytologic examination of the bone marrow and peripheral blood. Most patients are elderly with the vast majority diagnosed after the age of 60 years. Myelodysplastic syndromes (MDS) are a complex set of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations, ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML). In this review, we explore the utility of immune checkpoint inhibitors in MDS and current research evaluating their efficacy. Several trials are looking at the efficacy of these agents in MDS, as frontline therapy and in relapse, both as monotherapy and in combination with other drugs. Epigenetic modification via immune check point inhibition, while well established as a treatment method for advanced solid tumors, is a new approach being considered in hematologic malignancies including high risk MDS. This has led to rigorous investigations on the role of immunomodulatory drugs as potential treatment options. Several immune mechanisms have been identified in MDS, suggesting that immune dysregulation might be at least partially implicated in its pathogenesis. Studies have shown associations between MDS and other autoimmune diseases. MDS result from genetic and epigenetic derangements in clonal cells and their surrounding microenvironments. Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML).

Dysmantle kappa checkpoint