Retinoic acid and 6-formylindolo(3,2-b)carbazole (FICZ) combination therapy reveals putative targets for enhancing response in non-APL AML

Abstract

In non-APL AML, identification of a signaling signature would predict potentially actionable targets to enhance differentiation effects of all-trans-retinoic acid (RA) and make combination differentiation therapy realizable. Components of such a signaling machine/signalsome found to drive RA-induced differentiation discerned in a FAB M2 cell line/model (HL-60) were further characterized and then compared against AML patient expression profiles. FICZ, known to enhance RA-induced differentiation, was used to experimentally augment signaling for analysis. FRET revealed novel signalsome protein associations: CD38 with pS376SLP76 and caveolin-1 with CD38 and AhR. The signaling molecules driving differentiation in HL-60 cluster in non-APL AML de novo samples, too. Pearson correlation coefficients for this molecular ensemble are nearer 1 in the FAB M2 subtype than in non-APL AML. SLP76 correlation to RXRα and p47phox were conserved in FAB M2 model and patient subtype but not in general non-APL AML. The signalsome ergo identifies potential actionable targets in AML.

Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation

“…For example, our laboratory reported that the SFK inhibitors PP2, dasatinib, and bosutinib modulate MAPK signaling and enhance the therapeutic effects of ATRA in various myeloid leukemia cells [9,40]. We have also found that AhR ligands, specifically FICZ and VAF347, used with ATRA enhance induced differentiation [57,58]. www.oncotarget.com…”

“…Such therapies hold the promise of both overcoming resistance and mitigating the incidence of retinoic acid syndrome, a potentially fatal cardio-pulmonary pathological sequela of ATRA therapy, by reducing the effective dose of ATRA needed. Much effort has been devoted to identifying novel drugs with specific targets that would increase the therapeutic efficiency of ATRA [54][55][56][57][58]. In a series of studies, we have established that ATRA-induced differentiation and cell cycle arrest of a FAB M2 cell line model requires formation and activation of a macromolecular signaling complex, a signalsome, that incorporates a number of signaling molecules associated with MAPK pathway signal transduction as well as unexpected components, in particular the IRF-1 and AhR transcription factors [10,57].…”

Aryl hydrocarbon receptor (AHR) functions in infectious and sterile inflammation and NAD+-dependent metabolic adaptation

“…AHR is also operating by non-genomic signaling including protein kinases (Puga et al 2009). For example, it operates as component of E3 ubiquitin ligases (Ohtake et al 2009) and of a signalsome (Bunaciu et al 2019). Furthermore, AHR often operates in cross-talk with other transcription factors including Nrf2, the key protector against oxidative stress (Kensler et al2007) and NF-κB (Vogel et al 2014).…”

“…This process has been shown to depend on calcium mobilization mediated by cyclic ADP-ribose (Partida-Sanchez et al 2001). Interestingly, CD38 together with AHR is a constituent of a signalsome (Bunaciu et al 2019), probably regulating microbial defense.…”

Depleting interferon regulatory factor‐1(IRF‐1) with CRISPR/Cas9 attenuates inducible oxidative metabolism without affecting RA‐induced differentiation in HL‐60 human AML cells

“…HL-60 is a myelo-monocytic (granulocyte-monocyte) precursor cell that bears fidelity to a RA-responsive t (15,17)-negative subtype of AML. 16,40 Interferon is a regulator of myelo-monopoiesis. The primary mediator of the cellular effects of interferon is the IRF-1 transcription factor.…”