What is RARA?

Retinoic acid receptor alpha

RARA is the gene encoding for retinoic acid receptor alpha (RARα), a nuclear hormone receptor transcription factor, which when bound by RA (retinoic acid), acts as a transcription switch for myeloid differentiation. When overexpressed and not bound to ligand, RARα suppresses myeloid differentiation and maturation. This lack of normal cell differentiation leads to a lack of functional, mature cells1,2

Why does RARA matter?


RARA gene overexpression impairs cell function and is a key driver of HR-MDS in ~50% of newly diagnosed cases3

RARA can spell danger when it’s overexpressed1

RARA overexpression can result in an imbalance of RARα to RA. When there’s too much RARα and not enough RA, suppression of myeloid differentiation and maturation occur.

Watch how RARA overexpression can drive HR-MDS

Normal RARA Overexpression
Normal RARA overexpression
Normal RARA overexpression
RARA Overexpression in Mds
Excess of unbound RARα suppresses differentiation
RARA overexpression in MDS
RARA overexpression in MDS
  • There are 3 retinoic acid receptors (RARs) α, β, and γ, which are members of the nuclear receptor superfamily4
  • RARα is implicated in the pathogenesis of HR-MDS and AML1,5
    • Approximately 50% of patients with HR-MDS and ~30% of patients with AML are positive for RARA overexpression3,6
  • It is important to note that RARA overexpression in HR-MDS is distinct from the PML-RARA translocation in APL5,7

Further research into RARA overexpression aims to unlock new ways of potentially restoring normal hematopoiesis in a large subset of patients1

Hope for a brighter tomorrow

RARA gene overexpression defines a novel subset of patients with HR-MDS1,8

The importance of RARA overexpression in this patient group provides rationale for research into a different therapeutic approach. To learn about the crucial role RARA plays in HR-MDS, click here.1

RARA overexpression
is a key driver of HR-MDS in


of newly diagnosed cases3

SYROS is committed to keeping you up to date on the latest research related to HR-MDS

AML, acute myelodysplastic syndrome; APL, acute promyelocytic leukemia; HR-MDS, higher-risk myelodysplastic syndrome; PML, progressive multifocal leukoencephalopathy; RARA, retinoic acid receptor alpha.

References: 1. McKeown MR, Corces MR, et al. Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist. Cancer Discovery. 2017;7(10):1136-1153. 2. McKeown MR, Johannessen L, et al. Antitumor synergy with SY-1425, a selective RARα agonist, and hypomethylating agents in retinoic acid receptor pathway activated models of acute myeloid leukemia. Haematologica. 2019;104:e138-e142. 3. RARA-positivity based on Syros data on file from Study SY-1425-201 and the SELECT-MDS-1 Study (27May2022) from over 175 patients with MDS. 4. Parrado A, Despouy G, et al. Retinoic acid receptor α1 variants, RARα1△β and RARα1△βC, define a new class of nuclear receptor isoforms. Nucleic Acids Research. 2001;29(24):4901-4908.
5. Visconte V, Tiu RV, et al. Pathogenesis of myelodysplastic syndromes: an overview of molecular and non-molecular aspects of the disease. Blood Research. 2014;49(4):216-227. 6. Clinical Study SY-1425-201 Protocol. Syros Pharmaceuticals, Inc. 7. Liquori A, Ibañez M, et al. Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene. Cancers. 2020;12(624):1-22. 8. Vigil CE, Jurcic J, et al. RARA Pathway Activation Biomarkers in Study SY-1425-201 Define a New Subset of AML and MDS Patients and Correlate with Myeloid Differentiation Following Ex Vivo SY-1425 Treatment. Abstract 882. Presented at ESH. 2017:1.