LARP7 - the clamp on the 3' end of 7SK, whose human loss-of-function phenotype is dwarfism and intellectual disability rather than cancer
also called LARP7 · PIP7S · HDCMA18P · La-related protein 7
LARP7 grips the tail of the 7SK RNA and keeps the whole particle from falling apart; without it the RNA is degraded. Children born with two broken copies have severe growth failure and intellectual disability, which is the clearest evidence that this brake matters in a living human.
The same thing, for a scientist
LARP7 (UniProt Q4G0J3, 582 aa) binds the highly conserved 3' U-rich stretch of 7SK through its xRRM and is the **stable** component of the particle: it remains on 7SK after P-TEFb and HEXIM1 leave, immunodepleting LARP7 removes most cellular 7SK, and LARP7 knockdown lowers steady-state 7SK, transiently raises free P-TEFb and then reduces total P-TEFb protein [E1][E2]. Reducing LARP7 enhances transcription from cellular Pol II promoters and from a Tat-dependent HIV-1 promoter, so LARP7 is a negative transcriptional regulator acting through the 7SK RNP [E2]. Biallelic loss-of-function mutations in LARP7 cause Alazami syndrome - facial dysmorphism, severe intellectual disability and primordial dwarfism - with 7SK levels tightly linked to LARP7 expression across cell lines [E3]. That is the in-vivo consequence of partially dismantling the reservoir in a human, and it is a developmental syndrome, not a cancer predisposition. In this project's own dependency data LARP7 is unremarkable: mean Chronos -0.129 across 1,208 lines, rank 6,009 of 17,728, no lineage split [E4], and it is well expressed in every KMT2A-rearranged panel line (median 44.2 nTPM) [E5].
Why 'destroy the reservoir' is not the same intervention as 'fill the reservoir'
LARP7 is the cleanest demonstration that the 7SK snRNP is a stabiliser as well as an inhibitor. Knocking it down raises free P-TEFb at first and then lowers total P-TEFb protein, because the core holds the kinase in the nucleus 1. Any plan that treats 'remove the brake' and 'release the brake' as interchangeable will be wrong about the second half of the time course.
The same asymmetry is the reason the Alazami phenotype is informative. If losing the reservoir simply unleashed elongation, one would expect proliferative disease; what is observed is growth failure. The reservoir's in-vivo job appears to be to keep P-TEFb available and correctly partitioned, not merely to suppress it.
Nothing about LARP7 has been measured in leukaemia
Searching PubMed for (MLL OR KMT2A) AND LARP7 returns one record, a CDK9 review that mentions both in passing 6. There is no LARP7 knockdown, no LARP7 level, and no 7SK abundance measurement in any KMT2A-rearranged cell. This is a bounded absence, not an argument that LARP7 is irrelevant.
| uniprot | Q4G0J3 |
|---|---|
| length AA | 582 |
| gene symbol | LARP7 |
| uniprot verified | Q4G0J3 = LARP7_HUMAN, primary gene name LARP7, 582 aa, Homo sapiens; UniProt REST fetched and read back 2026-09-20 |
| role | binds the 3' U-rich end of 7SK through its xRRM; stable core component; chaperones and stabilises the RNA |
| human lof phenotype | Alazami syndrome (biallelic LOF): facial dysmorphism, severe intellectual disability, primordial dwarfism (PMID 22865833) |
| breakpoint side | not applicable - no documented KMT2A contact |
essentiality — the numbers behind the chart
{
"chronos_mean": -0.1286,
"n_lines": 1208,
"chronos_mean_kmt2ar_myeloid": -0.1292,
"chronos_mean_kmt2ar_lymphoid": -0.0869,
"chronos_mean_other_leukemia": -0.0979,
"scan_rank": 6009,
"scan_n_genes": 17728
}expression hpa celline nTPM — the numbers behind the chart
{
"SEM": 66.6,
"RS4;11": 32.2,
"MV4-11": 64,
"THP-1": 43.4,
"NOMO-1": 35.4,
"MOLM-13": 58.9,
"OCI-AML-2": 44.2,
"median": 44.2
}leukaemia literature
{
"query": "(MLL OR KMT2A) AND LARP7",
"records": 1,
"date": "2026-09-20",
"note": "the single hit is a CDK9 review"
}related entries
[ "protein-7sk-snrnp", "noncoding-rn7sk", "gene-mepce" ]
depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.12,
"chronos_mean_other_leukaemia": -0.0956,
"difference": -0.0244,
"pan_essentiality_all_lines": -0.1286,
"selectivity_rank": 6009,
"rank_denominator": 17728,
"provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
"how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}- Dismantling the reservoir lowers total P-TEFb after it first raises the free pool, so the direction of any LARP7-directed effect depends entirely on when you look.
- The human phenotype of losing this gene is primordial dwarfism and severe intellectual disability. Whatever the reservoir does, it is required for normal development, which caps how far it can be perturbed therapeutically.
- Is LARP7 protein, or 7SK abundance, different in KMT2A-rearranged blasts? Neither has ever been measured in one.
- Do Alazami syndrome patients have any haematological phenotype at all? The reports describe growth and neurology; blood counts are not systematically reported.
- Does LARP7 knockdown in a KMT2A::AFF1 line raise or lower fusion target-gene output, given that it does both to P-TEFb on different timescales?
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated; immunodepleting LARP7 depletes most cellular 7SK regardless of the other components, and LARP7 or 7SK knockdown initially increases free P-TEFb and ultimately decreases total P-TEFb protein levels.
LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated. · Krueger BJ, Jeronimo C, Roy BB, Bouchard A, Barrandon C, Byers SA, Searcey CE, Cooper JJ, Bensaude O, Cohen EA, Coulombe B, Price DH · Nucleic Acids Res 2008What this evidence cannot show
Human cell lines, glycerol gradients and siRNA; no haematopoietic or leukaemia cell.
Evidence that argues against this (1)
- The independent identification of LARP7 emphasises the opposite consequence - that reducing LARP7 enhances Pol II transcription - so the same manipulation reads as derepression on one timescale and as P-TEFb loss on another. Markert A et al. 2008
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
LARP7 binds the highly conserved 3' U-rich stretch of 7SK RNA, is an integral part of the 7SK RNP, remains associated with 7SK on stimulation while P-TEFb is released, and its reduction by RNA interference enhances transcription from cellular Pol II promoters and from a Tat-dependent HIV-1 promoter.
The La-related protein LARP7 is a component of the 7SK ribonucleoprotein and affects transcription of cellular and viral polymerase II genes. · Markert A, Grimm M, Martinez J, Wiesner J, Meyerhans A, Meyuhas O, Sickmann A, Fischer U · EMBO Rep 2008What this evidence cannot show
Human cell lines; the transcriptional effects are reporter and endogenous-gene measurements after RNAi, with no leukaemia context.
Evidence that argues against this (1)
- The same knockdown eventually lowers total P-TEFb, so an increase in transcription measured early does not predict the steady state. Krueger BJ et al. 2008
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
A biallelic loss-of-function mutation in LARP7 causes a syndrome of facial dysmorphism, severe intellectual disability and primordial dwarfism, and 7SK levels are tightly linked to LARP7 expression across cell lines, with LARP7 ubiquitously expressed in the mouse embryo.
Loss of function mutation in LARP7, chaperone of 7SK ncRNA, causes a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism. · Alazami AM, Al-Owain M, Alzahrani F, Shuaib T, Al-Shamrani H, Al-Falki YH, Al-Qahtani SM, Alsheddi T, Colak D, Alkuraya FS · Hum Mutat 2012What this evidence cannot show
A single large consanguineous Saudi family in the founding report, with subsequent independent families reported since. The phenotype is developmental; leukaemia is not part of it, but a rare syndrome is also not powered to detect a modest cancer risk.
Evidence that argues against this (1)
- 7SK also has a P-TEFb-independent role competing with HMGA1-mediated transcriptional regulation, which the founding report names explicitly, so the syndrome cannot be attributed wholly to P-TEFb dysregulation. Alazami AM et al. 2012
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
LARP7 has mean Chronos -0.129 across 1,208 DepMap lines and ranks 6,009th of 17,728, with the KMT2A-rearranged myeloid half at -0.129 and the lymphoid half at -0.087 against -0.098 in other leukaemia lines.
DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API, re-queried for this beat on 2026-09-20 and split by lineage inside the KMT2A-rearranged arm; genome-scale ranks read from this repository's analyses/depmap-kmt2a-selective-scan-full/results.json (17,728 genes, 1,208 lines) · Broad Institute DepMap; Open Targets Platform; Oncofusion KG internal scan · Databases 2026What this evidence cannot show
Six myeloid and four lymphoid lines; every value is near zero, so this is an absence of a dependency rather than a measured effect. A gene whose loss destabilises both its RNA partner and its client kinase may show a small net CRISPR score for reasons that have nothing to do with importance.
Evidence that argues against this (1)
- Biallelic LARP7 loss causes a severe human developmental syndrome, so a flat cell-line fitness score plainly under-reports the gene's biological weight. Alazami AM et al. 2012
- E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
LARP7 is detected in all seven KMT2A-rearranged panel lines the Human Protein Atlas carries, median 44.2 nTPM.
Human Protein Atlas cell-line RNA nTPM, rna_celline.tsv (24,315,372 rows, 1,206 cell lines), downloaded and filtered for this beat on 2026-09-20 · Human Protein Atlas · Database 2026What this evidence cannot show
Bulk poly-A cell-line RNA, not protein and not patient blasts.
Evidence that argues against this (1)
- LARP7 mRNA says nothing about 7SK abundance, which the same resource cannot measure at all. Human Protein Atlas 2026
- E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review
PubMed returns a single record for the query (MLL OR KMT2A) AND LARP7, which is a review of CDK9 signalling rather than a study of LARP7 in leukaemia.
CDK9: a signaling hub for transcriptional control. · Bacon CW, D'Orso I · Transcription 2019What this evidence cannot show
A counted absence is only as good as its symbol set. The query was run on 2026-09-20 with PubMed's own MLL/KMT2A expansion and the current HGNC symbol LARP7; the retired-symbol aliases PIP7S and HDCMA18P were not separately searched, and a paper framing the work at the level of '7SK snRNP' rather than naming LARP7 would not be retrieved.
Evidence that argues against this (1)
- This project has documented that complex-level phrases are unreachable from subunit symbols; a search on the complex name returns six records for '7SK snRNP AND leukemia', none of which is a KMT2A study either, but the enumeration is still symbol-bounded. He N et al. 2011
stable core component; clamps the 3' U-rich end of 7SK
xRRM on the 3' poly-U; 7SK levels track LARP7 levels
- regulates →Plain-English: what transcription elongation is, and why a traffic light explains this leukemia
negative regulator of Pol II transcription through the 7SK RNP
cooperate to stabilise 7SK; LARP7 occludes MEPCE's catalytic centre in the assembled particle
supplies the epigenetics record gene-larp7 lacks: CTD-level readout, chromatin measurement owed