Haematologica: Mutations in RXRA renew interest in retinoids for acute myeloid leukemia

For acute myeloid leukemia (AML) treatment, the "one-size-fits-all" idea is clearly outdated: future treatments will depend on phenotype or genetically defined subtypes
.

The most striking example is acute promyelocytic leukemia (APL) driven by a PMLRARA fusion protein

All-trans retinoic acid (ATRA) and arsenic trioxide cured over 90% of patients with PML-dependent aging through PML-RARA-driven degradation, differentiation, and recovery

Therapeutic targeting of RXR may be a strategy to activate the target under the control of the RXR/RAR transcriptional complex

Hematopoietic cells and some AMLs express endogenous RXRA ligands

The first shows that in KMT2A-MLLT3-driven AML, rexinoids partially inhibit AML growth and initiate differentiation
.

Furthermore, genetic ablation of RXR accelerated AML growth, while concomitant activation of RXRA and RARA promoted differentiation or apoptosis

In a second study published last year in Haematologica, di Martino et al.
report an incidentally discovered activating mutation in RXRA (RXRA DT448/9PP) that potently activates rexinoid/retinoid downstream signaling and is sufficient to induce the death of KMT2A-MLLT3 transformed cells terminal differentiation
.

The C-terminal helix 12 or AF-2 helix of RXRA is a key factor in determining ligand-dependent transcriptional activity by controlling co-activator/co-repressor binding

Surprisingly, di Martino et al.
demonstrated that overexpression of RXRA DT448/9PP resulted in enhanced transcriptional activity, resulting in multiple differentiation features in KMT2AMLLT3-transformed AML cells, in particular loss of colony-forming ability
.

This constitutively active RXRA variant is completely independent of ligand-binding coactivators

Cannot abolish or further promote transactivation by selective antagonists of RXR or other nuclear receptors or their agonists, respectively

Figure: Schematic summary of the effect of constitutively active RXRA DT448/9PP
.

(A) Under normal conditions, the transcriptional activity of RXRA heterodimerization with other nuclear receptors (NR) including RARA is silenced due to co-repressor binding

 

Figure: Schematic summary of the effect of constitutively active RXRA DT448/9PP
.

(A) Under normal conditions, the transcriptional activity of RXRA heterodimerization with other nuclear receptors (NR) including RARA is silenced due to co-repressor binding

Figure: Schematic summary of the effect of constitutively active RXRA DT448/9PP

These intriguing observations suggest that even though rexinoids and retinoids act synergistically on myeloid differentiation in these AMLs, a more profound 'unconventional' activation of RXRA can initiate terminal differentiation, and this major transcriptional regulatory complex deserves further study to decipher it How it becomes so potent in the absence of ligand, future studies should determine which AML exhibits this high sensitivity to RXRA signaling
.

The retinoid sensitivity seen in non-APL AML is especially important in the context of combination therapy
.

More profound "unconventional" activation of RXRA can initiate terminal differentiation,

 

Original source:

Qiu F, de The H.
An exciting RXRA mutant revives interest in retinoids for acute myeloid leukemia.
Haematologica 2021;107(2):354-355; https://doi.
org/10.
3324/haematol.
2021.
279152.
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