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Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation. | LitMetric

AI Article Synopsis

  • All-trans retinoic acid (ATRA) has been effective in treating M3 acute promyelocytic leukemia, but its use in other leukemia types hasn't shown strong results due to other cancer-driving signals.* -
  • The study aimed to explore the combination of JAK1 inhibition (via INCB52793) with ATRA as a new treatment strategy for non-M3 acute myeloid leukemia, assessing its effects on cell cycle and apoptosis.* -
  • Results showed that combining JAK1i with ATRA led to enhanced myeloid differentiation and reduced leukemic cell growth, suggesting a promising approach for treating certain leukemia cases.*

Article Abstract

Background: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis.

Objective: While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML).

Methods: Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts.

Results: Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion.

Conclusions: JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667588PMC
http://dx.doi.org/10.1007/s11523-021-00830-5DOI Listing

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