CXXC5 (RINF) - the one CXXC reader measurably down-regulated in KMT2A-rearranged AML, which is the only direction-of-change any family member has in this disease
also called CXXC5 · RINF · retinoid-inducible nuclear factor · CF5 · WID · CXXC-type zinc finger protein 5
CXXC5 reads unmethylated CG islands and escorts the demethylating enzyme TET2 to them. Its gene sits in the piece of chromosome 5 that is deleted in some myeloid cancers, and - the reason it matters here - its message is specifically turned down in leukaemias carrying a KMT2A rearrangement.
The same thing, for a scientist
CXXC5 (Q7LFL8) is **322 aa** with a CXXC-type zinc finger at **256-297**; its curated DOMAIN comment states the CXXC mediates binding to CpG-DNA, and unlike CXXC4 its nuclear location is **ECO:0000269, experimental** [E1]. Its mechanism in the family is escorting: CXXC5 is responsible for the recruitment of **TET2** to maintain hypomethylation of a subset of CpG islands, with the *Irf7* CGI as the worked locus, and *Cxxc5*-deficient mice show aberrant methylation of that island and impaired IRF7 expression [E2]. In embryonic stem cells Rinf binds chromatin at the promoters and enhancers of *Tet1*, *Tet2* and pluripotency genes, overlaps Nanog, Oct4, Sox2, Tet1 and Tet2 occupancy, and forms a complex with them [E3]. **The reason this entry matters more than its neighbours: CXXC5 is the only member of the twelve with a measured, direction-specified change in KMT2A-rearranged disease.** Kuhnl et al. report *CXXC5* mRNA **down-regulated in AML with MLL rearrangements**, alongside t(8;21) and GATA2-mutant AML, with evidence for epigenetic silencing by promoter methylation; lower expression predicted lower relapse and better overall and event-free survival independent of cytogenetic and molecular risk, and functionally CXXC5 inhibited leukaemic proliferation and Wnt signalling, which they read as a tumour-suppressor role [E4]. An independent 594-patient cohort found high *CXXC5* associated with **decreased** overall survival and an anti-apoptotic effect on knockdown, and argued for CXXC5 as a therapeutic target [E5] - **the two cohorts agree on the direction of the prognostic association and disagree on what it means functionally**, which is recorded here rather than resolved. *CXXC5* was originally cloned as RINF, a retinoid-responsive gene at 5q31 with a regulatory role in normal and tumoral myelopoiesis [E6]. DepMap shows nothing (difference +0.010, rank 10,398 of 17,728) [E7].
This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.
I have never read one of these pictures before
A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.
Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.
Anything in yellow sticks is a bound small molecule, which is usually the drug.
Down in KMT2A-rearranged AML - the beat's one directional fact
The dispatch for this beat asked whether the CXXC address is contested. Across twelve family members, exactly one has a measured change in expression specific to KMT2A-rearranged leukaemia, and it is a decrease: CXXC5 mRNA is down-regulated in AML with MLL rearrangements 4. The same study finds promoter methylation as a silencing mechanism and shows CXXC5 inhibiting leukaemic proliferation.
Read conservatively, that is a gene-expression association in one adult AML cohort with no mechanism connecting it to the fusion. Read as the beat's question, it is the only observation in the family with the right shape: a competitor for the unmethylated-CpG address is removed in the disease where the fusion occupies that address. The hypothesis hyp-the-cxxc-address-is-a-contested-resource treats it as the single best supporting datum and states plainly what it is not - it is not causality, not fusion-driven, not shown in infants, and not accompanied by any occupancy measurement.
The null matters here and is easy to state. CXXC5 is also down in t(8;21) and in GATA2-mutant AML in the same analysis 4, neither of which is KMT2A-rearranged. So the change is not specific to this fusion, and a claim that the fusion clears its competitor has to explain the other two subtypes. That observation alone moves the confidence from strong to moderate.
Two cohorts, one direction, two interpretations
| n | finding | authors' reading | |
|---|---|---|---|
| Astori et al. 2013 5 | 594 primary AML | wide variation in CXXC5; high mRNA associated with decreased overall survival on intensive chemotherapy; knockdown increases chemotherapy-induced apoptosis | CXXC5 is anti-apoptotic and is a therapeutic target |
| Kuhnl et al. 2015 4 | large AML cohort with expression profiling | low expression predicts lower relapse and better OS and EFS, independent of risk group; CXXC5 inhibits proliferation and Wnt signalling; silenced by promoter methylation | CXXC5 is a tumour suppressor |
The prognostic direction is the same in both - more CXXC5, worse outcome. The mechanistic readings are opposite: a target to knock down, versus a suppressor whose loss defines a better-outcome subgroup. Both are cited here at moderate and neither is used to support a mechanism. What would resolve it is a CXXC5 degron in a KMT2A-rearranged line with proliferation, apoptosis and CpG-island methylation read out together; neither study does that.
The alias trap, measured
RINF is a contaminated token. RINF[tiab] returns 62 records and the top twelve titles are dominated by bioelectrical impedance work - 'R-infinity', the extrapolated resistance at infinite frequency - across critical care, rat models, green turtles and grapevines. Only about a third of the visible records are the CXXC5 protein. CXXC5[tiab] returns 131 and is clean.
This is the same shape as RD for NELFE and U19 for EAF2 that this project has logged before: a short acronym in a field with its own vocabulary, inflating a count that looks healthy. It is proposed as a new row for data/symbol-collisions.json; see the memo. The registry was grepped for CXXC5 and RINF before the first query and contained neither.
| uniprot | Q7LFL8 |
|---|---|
| gene symbol | CXXC5 |
| protein name | CXXC-type zinc finger protein 5 |
| length AA | 322 |
| alphafold ID | AF-Q7LFL8-F1 |
| accession resolution | UniProt REST gene_exact:CXXC5 AND organism_id:9606 AND reviewed:true, run 2026-09-21; one row; primary gene name read back as CXXC5 and length 322 from the same fetched record. |
| alias hazard | RINF[tiab] returns 62 records dominated by bioelectrical-impedance 'R-infinity'; title-check every hit. CXXC5[tiab] returns 131 and is clean. |
| cytoband | 5q31.2-5q31.3, within the region deleted in del(5q) AML and MDS |
| function | CpG-island reader that recruits TET2 to maintain CpG-island hypomethylation; in ES cells binds Tet1/Tet2 and pluripotency gene regulatory regions; modulates Wnt, BMP and NF-kappa-B signalling |
| classification | CXXC-family reader acting as a TET2 escort in trans; the only family member with a measured expression change specific to leukaemia subtypes including KMT2A-rearranged AML |
| shown for fusion | AML with MLL rearrangements, as an expression DOWN-regulation with promoter methylation - shared with t(8;21) and GATA2-mutant AML, so not fusion-specific; no functional or occupancy experiment in any KMT2A fusion system |
| cell type evidence | primary human AML blasts (two cohorts, 594 and a large expression series); human CD34+ progenitors and APL lines (RINF discovery); mouse plasmacytoid dendritic cells and ES cells. No infant material and no KMT2A::AFF1 system. |
| epigenetic readout | CpG-island methylation, specifically at Irf7; CXXC5 promoter methylation in AML |
| subnuclear localization | Chromatin-bound at promoters and enhancers of Tet1, Tet2 and pluripotency genes in mouse ES cells (PMID 31433977); nuclear localisation in human is ECO:0000269, cytoplasmic is ECO:0000250. No human subnuclear compartment data. Never imaged in any KMT2A-fusion cell. |
| cell type | Primary human AML blasts (two adult cohorts, n = 594 and a large expression series including MLL-rearranged cases); human CD34+ progenitors and APL lines; mouse plasmacytoid dendritic cells and ES cells. No infant material and no KMT2A::AFF1 system. |
aliases retired or alternate
[ "RINF", "CF5", "WID", "PM08" ]
domains
[
{
"name": "CXXC (CpG-binding zinc finger)",
"start": 256,
"end": 297,
"pfam": "PF02008"
}
]localization
{
"subcellular": "nucleus (ECO:0000269); cytoplasm (ECO:0000250, by similarity)",
"subnuclear": "chromatin-bound at promoters and enhancers in mouse ES cells; no human subnuclear data",
"localization_shown_for_fusion": "NO"
}essentiality
{
"depmap_scan": "analyses/depmap-kmt2a-selective-scan-full",
"difference_kmt2a_r_minus_other": 0.0095,
"mean_kmt2a_rearranged": 0.0613,
"mean_other_leukemia": 0.0518,
"pan_essentiality_all_lines": 0.0656,
"n_all_lines": 1208,
"rank_of_17728": 10398,
"percentile": 58.653,
"expression_caveat": "if CXXC5 is silenced by promoter methylation in KMT2A-rearranged AML, a knockout screen in those lines is uninformative",
"release_note": "Open Targets dataVersion 26.06, read 2026-09-21"
}- If CXXC5 is a tumour suppressor silenced in KMT2A-rearranged AML, a therapy that re-expresses it would be the intervention - and a hypomethylating agent does exactly that non-specifically, which is a testable and cheap prediction nobody has tested.
- The two AML cohorts imply opposite interventions from the same prognostic direction: knock CXXC5 down, or restore it. Acting on either without resolving the discrepancy is a coin flip.
- CXXC5 sits in the 5q31 deletion. Any patient with del(5q) has already lost a copy, so a CXXC5-directed strategy has a built-in subgroup that cannot respond the same way.
- Is CXXC5 down-regulated in infant KMT2A::AFF1 B-ALL as it is in adult MLL-rearranged AML, and is its promoter methylated there? Both are answerable from existing infant ALL expression and methylation data.
- Is the down-regulation a consequence of the fusion or of the cell of origin? An inducible fusion in a CXXC5-expressing progenitor separates them, and the shared down-regulation in t(8;21) and GATA2-mutant AML argues for the second.
- CXXC5 escorts TET2 to CpG islands. If CXXC5 is silenced, does TET2 activity at CpG islands fall in KMT2A-rearranged cells - producing a methylome change with no TET2 mutation at all? That would rescue the methylome argument that the TET2 co-mutation data kills.
- Are the tumour-suppressor and anti-apoptotic readings of CXXC5 reconcilable, or does one cohort have a confound the other does not?
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
CXXC5 (Q7LFL8) is 322 aa with a CXXC-type zinc finger at 256-297, its curated DOMAIN comment states the CXXC mediates binding to CpG-DNA, and its nuclear localisation carries experimental evidence (ECO:0000269) while its cytoplasmic term is ECO:0000250.
UniProtKB Q7LFL8 (CXXC5_HUMAN), CXXC-type zinc finger protein 5 / Retinoid-inducible nuclear factor (RINF) · UniProt Consortium · UniProtKB 2026What this evidence cannot show
Fetched 2026-09-21; accession resolved by gene_exact:CXXC5 AND organism_id:9606 AND reviewed:true, one row, primary gene name read back as CXXC5 and length 322 from the same record. UniProt's FUNCTION comment is hedged throughout ('may indirectly participate'), which is unusual and reflects a literature with many reported activities and few decisive ones.
Evidence that argues against this (1)
- Several of CXXC5's annotated functions - NF-kappa-B and MAPK activation, ATM phosphorylation, COX4I2 repression under hypoxia - are not chromatin-reader functions at all, so a CXXC-centric reading of this protein is a partial one. UniProt Consortium 2026
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
CXXC5 is responsible for recruiting the DNA demethylase TET2 to maintain hypomethylation of a subset of CpG islands; genetic ablation of CXXC5 causes aberrant methylation of the CpG island within Irf7 and impaired IRF7 expression in steady-state plasmacytoid dendritic cells.
Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs. · Ma S, Wan X, et al. · J Exp Med 2017What this evidence cannot show
Mouse plasmacytoid dendritic cells and viral-infection models; the mechanism is worked out at one CpG island. The 'subset of CpG islands' claim rests on genome-wide methylation in one cell type. No malignant or KMT2A-rearranged system.
Evidence that argues against this (1)
- In embryonic stem cells the same protein is reported to regulate Tet1 and Tet2 at the level of transcription rather than to escort TET2 to a locus, so the mechanism may be cell-type-specific. Ravichandran M et al. 2019
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In mouse embryonic stem cells Rinf/CXXC5 binds chromatin and is enriched at promoters and enhancers of Tet1, Tet2 and pluripotency genes, overlapping Nanog, Oct4, Sox2, Tet1 and Tet2 occupancy, and forms a complex with Nanog, Oct4, Tet1 and Tet2.
Rinf Regulates Pluripotency Network Genes and Tet Enzymes in Embryonic Stem Cells. · Ravichandran M, Lei R, et al. · Cell Rep 2019What this evidence cannot show
Mouse ES cells. The complex is shown biochemically in ESC extracts; the occupancy overlap is a genome-wide correlation, and co-occupancy of active promoters is a weak claim on its own because most chromatin factors overlap there.
Evidence that argues against this (1)
- Co-occupancy at active promoters is close to a base rate in ESC ChIP data; without a null for how much overlap two unrelated promoter-binding factors would show, the overlap statistic carries little information. Ravichandran M et al. 2019
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
CXXC5 mRNA is down-regulated in AML with MLL rearrangements, as well as in t(8;21) and GATA2-mutant AML, with evidence for epigenetic silencing by promoter methylation; expression below the median predicted lower relapse and better overall and event-free survival independent of cytogenetic and molecular risk, and CXXC5 inhibited leukaemic proliferation and Wnt signalling.
Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia. · Kühnl A, Valk PJ, et al. · Blood 2015What this evidence cannot show
Adult AML expression cohorts; the MLL-rearranged group is not broken out by partner and is not infant disease. The down-regulation is an mRNA association, with no protein measurement and no occupancy measurement, and it is shared with two non-KMT2A subtypes so it is not fusion-specific. The functional work is in cell lines.
Evidence that argues against this (1)
- An independent 594-patient cohort reads the same prognostic direction as evidence that CXXC5 is anti-apoptotic and should be targeted, i.e. an oncogenic rather than a tumour-suppressor role. Astori A et al. 2013
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Across 594 primary human AML samples, high CXXC5/RINF mRNA was associated with decreased overall survival in patients receiving intensive chemotherapy, including within normal-karyotype and core-binding-factor subgroups, and CXXC5 knockdown increased susceptibility to chemotherapy-induced apoptosis.
CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia. · Astori A, Fredly H, et al. · Oncotarget 2013What this evidence cannot show
Adult AML; expression measured on bulk leukaemic blasts. The apoptosis result is in AML cell lines. Prognostic associations in unselected cohorts are confounded by cytogenetics even when subgroups are examined, and no multivariate model against a modern risk classification is reported in the abstract.
Evidence that argues against this (1)
- Kuhnl et al. reach the opposite functional conclusion - CXXC5 as a tumour suppressor inhibiting proliferation and Wnt signalling - from the same direction of prognostic association. Kühnl A et al. 2015
- E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
CXXC5 was identified as RINF, a retinoid-responsive gene whose expression correlates with retinoid-induced differentiation of leukaemic cells and with cytokine-induced myelopoiesis of normal CD34+ progenitors, with shRNA evidence for a regulatory function in both normal and tumoral myelopoiesis; it maps to 5q31.3, a region frequently deleted in AML and MDS.
Functional involvement of RINF, retinoid-inducible nuclear factor (CXXC5), in normal and tumoral human myelopoiesis. · Pendino F, Nguyen E, et al. · Blood 2009What this evidence cannot show
Microarray discovery plus shRNA knockdown in leukaemic lines and primary CD34+ cells; 2009, before the CXXC domain's DNA-binding role in this protein was measured. The 5q31 location is a genomic fact, not evidence that CXXC5 is the 5q- target gene.
Evidence that argues against this (1)
- The 5q deletion in MDS spans many genes and the causal ones identified to date are RPS14 and CSNK1A1, not CXXC5; genomic co-location is not implication. Kühnl A et al. 2015
- E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
CXXC5 shows no dependency in KMT2A-rearranged cell lines: difference +0.0095, rank 10,398 of 17,728, pan-essentiality +0.0656.
Genome-wide KMT2A-rearranged selectivity scan, 17,728 genes (DepMap CRISPR Chronos via the Open Targets Platform GraphQL API) · Oncofusion knowledge-graph project · analyses/depmap-kmt2a-selective-scan-full/results.json, generated 2026-09-19; Open Targets dataVersion year 26 month 06, re-read from the API on 2026-09-21 2026What this evidence cannot show
The scan compares 11 Cellosaurus-annotated KMT2A-rearranged lines against 43 other leukaemia lines; none of the 11 is infant-derived and the arm is myeloid-enriched, so a difference mixes fusion status with lineage. Both the difference and the pan-essentiality across all 1,208 lines are quoted, because a gene required everywhere is not a selective dependency. Open Targets dataVersion 26.06; DepMap's own release identifier is not returned by that endpoint.
Evidence that argues against this (1)
- If CXXC5 is transcriptionally silenced in KMT2A-rearranged AML, a CRISPR knockout of an already-silenced gene has nothing to remove, and a near-zero gene effect is then expected regardless of biology. Kühnl A et al. 2015
- E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database
RINF is a contaminated search token: RINF[tiab] returns 62 records whose visible majority are bioelectrical-impedance studies using R-infinity, while CXXC5[tiab] returns 131 and is clean.
PubMed E-utilities esearch record counts with querytranslation inspected and every returned title read · Oncofusion knowledge-graph project · NCBI E-utilities, queries run 2026-09-21; exact query strings given in the caveat of each item that uses this source 2026What this evidence cannot show
Queries `RINF[tiab]` and `CXXC5[tiab]` run 2026-09-21; the top twelve RINF titles were read individually and the contamination fraction is estimated from them rather than from all 62. data/symbol-collisions.json was grepped for both tokens before the first query and contained neither.
Evidence that argues against this (1)
- Two genuine CXXC5 papers - the Haematologica erythroid study and the ESC Tet study - are reachable through RINF, so the token cannot simply be dropped from a name list. Ravichandran M et al. 2019
Reads unmethylated CpG islands and recruits TET2 to keep them hypomethylated - i.e. it maintains the chemical state the fusion's address depends on.
One of the eleven other human CXXC domains a ligand for this interface must discriminate against.
CXXC5 recruits TET2 to maintain hypomethylation of a subset of CpG islands - TET2's second in-trans route to the address.
One of the twelve human CXXC proteins.
The two small trans-acting TET escorts; in differentiating ES cells Idax and Rinf act together on Tet expression.