CCRL2 and who? An important driver in TP53-mutant myeloid leukemias

Mutations in tumor suppressor gene TP53 are associated with adverse outcomes in myeloid malignancies,^1,2 and are enriched in acute erythroleukemia.³ TP53-mutant myeloid neoplasms are characterized by resistance to current therapies and higher rates of relapse.¹ Recent studies have shown that a chronic inflammatory bone marrow microenvironment may drive progression of TP53-mutant myeloid leukemias.⁴ IFN-γ mediated JAK-STAT signaling has been implicated in progression of monocytic leukemias.⁵ The mechanistic link between the role of IFN-γ signaling and TP53-mutant leukemias is not well understood.

Previous work by Karantanos et al. showed that the C-C motif chemokine receptor-like 2 (CCRL2), a protein involved in activation of inflammatory signaling, is significantly up-regulated in blasts from patients with myelodysplastic syndromes (MDS) compared to de novo acute myeloid leukemia (AML) and healthy controls.⁶ Additionally, silencing of CCRL2 was sufficient to decrease MDS and AML cell growth and increase their sensitivity to azacitidine in vitro and in vivo.⁷ Given the significance of CCRL2 in these contexts, the authors seek to understand if it may be of similar importance specifically in TP53-mutant AML with erythroid differentiation.⁸

Assessment of publicly available data showed that AML with erythroid and megakaryocytic differentiation had higher CCRL2 expression compared to other AML subtypes in patient samples. Importantly, TP53-mutant AML had higher CCRL2 expression compared to TP53 wild-type (WT) AML. To investigate the role of CCRL2 in TP53-mutant AML, authors silenced CCRL2 in TP53-mutant AML and erythroleukemia cell lines, resulting in suppressed growth vitro and in vivo. In contrast, TP53-WT AML cells were not impaired by CCRL2 knockout (KO). These data suggest a functional role of CCRL2, specifically in TP53-mutant AML cells. To gain insights into the mechanistic link between CCRL2 and TP53-mutant leukemogenesis, authors pursued transcriptomic and phosphoproteomic studies comparing CCRL2 WT versus KO cells. Members of the IFN-γ signaling pathway were down-regulated upon CCRL2 KO. These findings are concordant with the previous work from this group, which showed that CCRL2 promotes JAK-STAT signaling.⁶ The authors also developed a doxycycline-inducible CCRL2 model and found that cells treated with doxycycline exhibited increased phosphorylation of STAT1 at Y701 and S727. When treated with a JAK2 inhibitor, Y701 phosphorylation decreased and S727 remained unchanged. These findings implicate CCRL2 in STAT1 signaling, a process that is, at least in part, reliant upon JAK2.

Next, the authors compared their CCRL2 KO transcriptomic data to published datasets and they uncovered a list of 18 genes which were associated with both CCRL2 and IFN-γ signaling. These genes were then used to score different AML subsets for their expression of these genes. In both patient samples and AML cell lines, acute erythroleukemia had consistently higher expression levels than other AML subtypes. Importantly, TP53-mutant AML scored higher than TP53-WT AML and healthy controls.

Based on the data showing increased STAT1 signaling driven by CCRL2 in TP53-mutant AML, the authors investigated whether this pathway depends on exogenous IFN-γ stimulation. Firstly, T cells sorted from TP53-mutant AML patients secreted lower levels of IFN-γ when compared to controls. In addition, treatment of CCRL2 KO cells with exogenous IFN-γ did not alter the expression of IFN-γ targets when compared to controls, which suggests that CCRL2 may be required for cell intrinsic effects of IFN-γ response. In consideration also of the previous work showing down-regulated IFNG gene expression in patients with TP53-mutant AML,⁵ this suggests that more work is needed to fully understand the role of exogenous IFN-γ in mediating the oncogenic effects of CCRL2 in TP53-mutant AML.

Patients with acute erythroleukemia and TP53-mutant AML often present with resistance to BH3 mimetic venetoclax.¹ The authors investigated the value of their CCRL2/IFN-γ gene expression score in predicting venetoclax response by using the Beat AML dataset. Patients with higher expression of the CCRL2/IFN-γ gene signature had higher IC₅₀ values with venetoclax when compared to patients with lower gene scores. They corroborated this finding by incubating CCRL2 KO cell lines with venetoclax and found they were more sensitive to the drug than CCRL2 WT, implicating CCRL2 in resistance to venetoclax treatment.

Figure 1.CCRL2 increases JAK-STAT1 signaling and drives venetoclax resistance in TP53-mutant acute myeloid leukemia. AML: acute myeloid leukemia.

In summary, Naji et al. highlight an important role for CCRL2 in TP53-mutant AML and acute erythroleukemia by establishing new mechanistic insights with CCRL2-regulated STAT signaling in high-risk subsets of AML (Figure 1). While these findings are interesting, additional experimental work is necessary to establish the link between IFN-γ, TP53 and CCRL2. It would be interesting to understand if CCRL2 is directly interacting with IFNGR, and whether the relationship between CCRL2 and downstream IFN-γ signaling is TP53-mediated. From a translational perspective, these results open up several avenues for further research. Firstly, CCRL2 may serve as a biomarker for identifying subsets of TP53-mutant myeloid neoplasms with heightened inflammatory signaling. Secondly, CCRL2-IFN-γ axis modulation could represent a novel therapeutic approach, particularly in a patient population with limited effective treatment options. Whether targeting CCRL2 directly, or indirectly modulating its ligands and signaling partners, can translate into clinical benefit remains to be determined.

Footnotes

• Received August 20, 2025
• Accepted August 29, 2025

Correspondence

C. Saygin caner.saygin@bsd.uchicago.edu

Disclosures

No conflicts of interest to disclose.

Contributions

OA and CS are joint authors of this editorial.

Funding

CS is supported by the Department of Defense Peer Reviewed Cancer Research Program (HT94252510221), the American Society of Hematology Scholar Award, the Leukemia Lymphoma Society Special Fellow Award, and the Leukemia Research Foundation Award.