Abstract
Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous malignant disorder characterized by abnormal proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs)
Most frequent alterations appear in genes expressing signaling proteins (e.g., KIT, FMS-like tyrosine kinase 3 (FLT3), NPM1, CEBPA), epigenetic modulators (e.g., EXH2, TET2, DNMT3A) or as chromosomal rearrangements that generate fusion transcripts of genes encoding for transcription factors
In de novo AML, constitutive activation of signal transducer and activator of transcription (STAT) can be achieved by auto- and paracrine factors such as IL-6, decreased expression of negative regulators such as SOCS1 or activating mutations in other upstream kinases such as FMS-like tyrosine kinase 3 (FLT3) [86]
Summary
Acute myeloid leukemia (AML) is a heterogeneous malignant disorder characterized by abnormal proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). The current World Health Organization (WHO) classification considers morphologic, cytogenetic and molecular genetic analysis, clinical history, and prognostic and immunophenotypic data. It defines specific disease entities by focusing on genetic subgroups: AML with recurrent genetic abnormalities (AML-RGA), AML with myelodysplasia-related changes (MDS-AML), therapy-related AML (tAML) and AML not otherwise specified (AML-NOS) [11]. Most frequent alterations appear in genes expressing signaling proteins (e.g., KIT, FLT3, NPM1, CEBPA), epigenetic modulators (e.g., EXH2, TET2, DNMT3A) or as chromosomal rearrangements that generate fusion transcripts of genes encoding for transcription factors. We present a comprehensive overview of clinically relevant inhibitors for AML patients, acting on JAK-STAT signaling
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