The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

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.

RNA N6-methyladenosine reader IGF2BP3 promotes acute myeloid leukemia progression by controlling stabilization of EPOR mRNA

“…The JAK/STAT signaling pathway has various biological effects, including cell growth or amplification, differentiation, inflammation, and apoptosis. The abnormal aberrant activation of the JAK/STAT signaling pathway is associated with the development of AML ( Venugopal, Bar-Natan & Mascarenhas, 2020 ), and JAK2 inhibitors can reverse this effect ( Habbel et al, 2020 ; Moser et al, 2021 ). Moreover, STAT5 is a potential target for patients with refractory and relapsed AML ( Brachet-Botineau et al, 2020 ; Page et al, 2012 ).…”

Signaling pathways governing the behaviors of leukemia stem cells

“…As a result, antisense oligonucleotide-regulated aberrant activation of the STAT3 pathway can be a promising approach to diminish AML and MDS stem cells. 181 Moreover, STAT5 has been shown to be involved in LSCs' self-renewal. 182 Hence, managing aggressive leukemia needs the repression of several pathways.…”

Advances in molecular characterization of myeloid proliferations associated with Down syndrome

“…JAK1-3 variants are identified in both ML-DS and TAM samples, however, gain-of-function mutations are only detected in ML-DS, highlighting that aberrant activation of JAK-STAT signaling is important for transition to leukemia ( Labuhn et al, 2019 ). The JAK family of tyrosine kinases (JAK1-3 and tyrosine kinase 2, TYK2) are pivotal mediators of growth factor and cytokine signaling, including downstream of thrombopoietin (TPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) ( De Castro et al, 2021 ; Moser et al, 2021 ). JAK1, JAK2 and TYK2, are ubiquitously expressed, whilst JAK3 is predominantly expressed in lymphoid and myeloid cells.…”

“…JAK3 mutations are more common than of other members of JAK family in ML-DS ( Labuhn et al, 2019 ). Under physiological conditions, JAK-STAT signaling is tightly controlled and involved in a wide range of fundamental biological processes, including cell proliferation, differentiation, apoptosis, inflammation, and blood production ( Park et al, 2016 ; De Castro et al, 2021 ; Moser et al, 2021 ). Normal megakaryopoiesis requires TPO-mediated STAT5 activation.…”