MCL1 - named in 34 entries of this graph with no entry of its own until now; a mitochondrial survival protein high in infant KMT2A-rearranged ALL, druggable, and so far undruggable in patients
also called MCL1 · MCL-1 · BCL2L3 · Bcl-2-like protein 3 · myeloid cell leukaemia-1 · Induced myeloid leukemia cell differentiation protein Mcl-1 · Q07820
MCL1 is a protein that sits on the mitochondria and stops a cell from killing itself, and infant KMT2A-rearranged leukaemia makes a lot of it - which is one reason steroids work badly in these babies. Drugs that block MCL1 kill these leukaemia cells beautifully in a dish, and in people they have so far mostly produced heart-muscle blood tests going up without much benefit.
The same thing, for a scientist
MCL1 (UniProt Q07820, 350 aa, primary gene name read back 2026-09-20; gene synonym BCL2L3) is an anti-apoptotic BCL-2 family protein that sequesters BH3-only and effector proteins at the outer mitochondrial membrane. It earns a metabolism-beat entry because it is the point where this disease's apoptotic and mitochondrial biology meet, and because the most recent mechanistic advance in the field is explicitly metabolic: **inhibiting electron transport chain complex I is synthetically lethal with MCL-1 inhibition**, acting through DELE1-dependent HRI activation of the integrated stress response and ATF4, with the authors framing the result for KMT2A-rearranged AML [E1]. In infant KMT2A-rearranged ALL, high MCL-1 expression was associated with prednisolone resistance in vitro and with poor in vivo prednisone response, and MCL-1 knockdown partially resensitised resistant cells [E2]. Pharmacologically, the MCL1 inhibitor S63845 is most potent against cell lines derived from infants with KMT2A-rearranged ALL, but a triple combination with venetoclax and dexamethasone - not MCL1 inhibition alone - is what matches induction chemotherapy in PDX models, while the venetoclax doublet killed 8 of 12 mice from tumour lysis syndrome [E3]. In paediatric AML, MIK665 has single-agent activity across cell lines and a subset of PDX [E4], and MCL1 inhibition potentiates MYB degradation [E5]. **The class has a clinical problem that is not a formulation problem**: two first-in-human MCL-1 inhibitor studies report cardiac troponin elevations with low response rates, and one concludes troponin release is likely a class effect of MCL-1 inhibition in humans [E6][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.
Why MCL1 belongs in the metabolic layer and not only in the apoptosis layer
Three reasons, in increasing order of strength.
- Location. MCL1 acts at the outer mitochondrial membrane, and a growing literature assigns it non-apoptotic mitochondrial functions in bioenergetics and mitochondrial morphology. That alone would be weak.
- The dependency is metabolically conditioned. The 2026 synthetic-lethal result is not a BH3-mimetic combination; it is a metabolic combination. Complex I inhibition creates the MCL-1 dependency by triggering the mitochondrial integrated stress response through DELE1 and HRI 1. The drug that creates the vulnerability is an OXPHOS inhibitor, which is the same class this graph already carries under
cell-state-oxphos-dependence. - The lineage split maps onto the metabolic split. The OXPHOS-dependent state is established in KMT2A-rearranged AML and inverted in KMT2A-rearranged B-ALL, where OXPHOS inhibition promotes the emergence of leukaemia-initiating cells. If MCL-1 dependence is created by complex I inhibition, then the same manoeuvre that makes myeloid disease MCL-1-dependent may be the manoeuvre that expands the initiating compartment in lymphoid disease. Nobody has tested this and it is the sharpest open question in this entry.
Consequence of the fusion programme, or independent dependency?
For MCL1 the honest answer is probably a consequence, but the primary citation usually given for that does not say so.
The 2026 infant paper states in its introduction that "MCL1 is a direct target gene of KMT2A fusion proteins" and cites, for that sentence, a paper whose title is MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation (Godfrey et al., Exp Hematol 2017) - which is about BCL2, not MCL1 3. This graph should therefore not carry "MCL1 is a direct KMT2A-fusion target gene" as an established fact on that chain of citation. What is directly measured is weaker and still useful: MCL-1 mRNA is significantly higher in MLL-rearranged infant ALL patients with a poor in vivo prednisone response than in good responders, and knockdown partially resensitises 2.
So: elevated in the disease, associated with a clinically important resistance phenotype, functionally contributing to it, and of unestablished direct transcriptional linkage to the fusion. That is a different and more defensible claim than the one in circulation.
The in vitro / in vivo inversion, which is the most decision-relevant thing here
In KMT2A-rearranged cell lines S63845 is potent, and the four most sensitive lines are all infant-derived 3. In mice, S63845 monotherapy gave no significant survival benefit at any of three doses; S63845 plus venetoclax did not beat venetoclax alone and induced lethal tumour lysis syndrome in 8 of 12 mice (67%) at 12.5 mg/kg or above; and only the triple with dexamethasone nearly doubled survival and matched a vincristine/dexamethasone/asparaginase induction regimen 3.
That pattern - strong in a dish, nothing as a single agent in an animal, lethal in the obvious doublet, effective only with a steroid - is the pattern a target has when the dish is measuring something the animal does not. It is also the pattern that predicts the clinical result the class has actually had 67.
Sensitivity did not correlate with MCL1 protein or mRNA level. BCL-XL mRNA correlated positively with the S63845 IC50 and KMT2A-rearranged cells had significantly lower BCL-XL protein, so the selectivity looks like reduced BCL-XL dependence rather than MCL1 overexpression 3. Any biomarker strategy built on measuring MCL1 is therefore contradicted by the pharmacology in the same paper that establishes the sensitivity.
| uniprot | Q07820 |
|---|---|
| length AA | 350 |
| alphafold ID | AF-Q07820-F1 |
| family | BCL-2 family, anti-apoptotic; outer mitochondrial membrane |
| resolution note | gene_exact:MCL1 AND organism_id:9606 AND reviewed:true returned 1 reviewed row on 2026-09-20; gene_primary read back as MCL1; length 350 aa asserted. Synonym BCL2L3 noted because the family's L-numbering is a known collision source. |
| graph status before this entry | named in 34 entries by word-boundary count on 2026-09-20 (plus 19 as 'MCL-1'), with no entry of its own; 5th on the named-but-unwritten queue |
| class toxicity | cardiac troponin elevation reported for AZD5991 and ABBV-467; described by one group as likely a class effect of MCL-1 inhibition in humans |
| biomarker status | no validated predictive biomarker; MCL1 level itself does NOT predict S63845 response in infant KMT2A-r ALL lines, low BCL-XL does better |
| direction in disease | pro-survival; high expression associated with prednisone resistance in MLL-rearranged infant ALL |
| subnuclear localization | NOT APPLICABLE as a resting address and UNPUBLISHED as a damage-state one. MCL-1's functional compartments are submitochondrial; the single nuclear report is damage-induced foci with no compartment named. This is a different statement from 'nobody has looked' - MCL-1's localisation has been dissected in detail and the answer was inside the mitochondrion. |
| shown for fusion | NO. (MCL1 OR "MCL-1")[tiab] AND (KMT2A OR MLL)[tiab] returns 37 records (PubMed esearch 2026-09-21), all pharmacology or dependency papers; the one squarely in the index disease - BCL-2 and MCL1 co-inhibition in infant KMT2A-rearranged ALL - reports drug-combination efficacy and contains no subcellular measurement. No fractionation, submitochondrial assignment or imaging of MCL-1 has been done in a KMT2A-rearranged cell. Zero in titles and abstracts; supporting figures not searched. |
inhibitors
[ "S63845", "MIK665 (S64315)", "AZD5991", "ABBV-467" ]
localization
{
"subcellular": "Mitochondrion, in TWO distinct submitochondrial pools from one gene. A full-length isoform sits in the OUTER mitochondrial membrane and behaves like the other anti-apoptotic BCL-2 proteins; an amino-terminally truncated isoform is imported into the mitochondrial MATRIX, where it is required for normal mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure and oligomeric ATP synthase. A minor nuclear pool is separately reported at sites of DNA damage. UniProt Q07820 was consulted only to confirm accession, primary gene name and length (350 aa); no localisation string was taken from it.",
"subnuclear": "essentially unpublished. The only nuclear observation read for this beat is that MCL-1 localises to sites of DNA damage and modulates the DNA damage response - a damage-induced focus, not a constitutive nuclear body, speckle, nucleolar or heterochromatin assignment. No subnuclear compartment has been assigned to MCL-1 in any source read here.",
"how_shown": "submitochondrial fractionation plus isoform-specific constructs and functional mitochondrial assays (PMID 22544066); N-terminal deletion mapping of localisation determinants (PMID 17823113); damage-induced focus formation (PMID 20647761)",
"systems": "mouse and human non-leukaemic cell systems for the matrix/outer-membrane split; no KMT2A-rearranged system anywhere",
"node": "localization-kat8-mof-has-a-mitochondrial-pool"
}localization counted absence
{
"query": "(MCL1[tiab] OR \"MCL-1\"[tiab]) AND (KMT2A[tiab] OR MLL[tiab])",
"records": 37,
"records_on_localization": 0,
"operand_controls": {
"MCL-1[ti] AND (matrix OR \"outer mitochondrial membrane\" OR localiz* OR nuclear)[ti]": 23
},
"date": "2026-09-21",
"tool": "PubMed E-utilities esearch",
"bound": "37 records title-checked; none is a localisation study. Zero in titles and abstracts; supporting figures not searched."
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -1.3071,
"chronos_mean_other_leukaemia": -0.8415,
"difference": -0.4656,
"pan_essentiality_all_lines": -0.7743,
"selectivity_rank": 18,
"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."
}- Cardiac troponin elevation has now been reported for two structurally distinct MCL-1 inhibitors in first-in-human studies, and one group concludes it is a class effect of MCL-1 inhibition rather than a compound liability. MCL1 is required for cardiomyocyte survival; this is the essential-function toxicity case, not an off-target case.
- The obvious combination - MCL1 inhibitor plus venetoclax - killed 8 of 12 mice from tumour lysis syndrome in infant KMT2A-rearranged ALL models. Efficacy in this disease may be inseparable from a lethal rate of blast killing.
- MCL1 monotherapy gave no survival benefit at any tested dose in vivo despite nanomolar in vitro IC50 values. The dish overstates this target.
- Resistance has an obvious pre-specified route: BCL-XL. The cells most sensitive to MCL1 inhibition are those with least BCL-XL, so upregulating BCL-XL is a single-step escape, and BCL-XL inhibition brings dose-limiting thrombocytopenia.
- Delivery and schedule: the only regimen that worked in infant models required three agents including a steroid, in babies under one year, where cumulative toxicity and long-term neurodevelopmental consequences of steroid exposure are already a live clinical concern.
- the matrix pool is not the apoptotic pool - An MCL1 inhibitor developed against the BH3 groove of the outer-membrane form will also engage the matrix-imported form, which is required for mitochondrial fusion, ATP production, membrane potential and cristae structure. Cardiac and haematopoietic toxicity from MCL1 inhibition is an essential-function toxicity in a compartment the antileukaemic rationale never invokes, and the two pools have never been separated in a KMT2A-rearranged cell.
- Is MCL1 a direct transcriptional target of KMT2A fusion proteins? The claim is in circulation and the citation chain behind it points at a BCL-2 enhancer paper. A fusion ChIP or CUT&RUN track at the MCL1 locus in SEM or RS4;11 would settle it in a day from existing public data.
- Does complex I inhibition create MCL-1 dependence in KMT2A::AFF1 B-lineage cells as it does in AML, or does it instead expand the leukaemia-initiating compartment as OXPHOS inhibition does in MLL-rearranged B-ALL? These two published results point in opposite directions and have never been run in the same system.
- Is the cardiac troponin signal separable from antileukaemic activity, or is it on-target mitochondrial toxicity in cardiomyocytes and therefore inseparable? A cardiomyocyte MCL1 dependency would make this a hard ceiling rather than a formulation problem.
- Why is low BCL-XL, rather than high MCL1, the correlate of MCL1-inhibitor sensitivity in KMT2A-rearranged cells? If reduced BCL-XL dependence is the real KMT2A-linked phenotype, then BCL-XL is the unwritten entry and MCL1 is the consequence.
- In a KMT2A-rearranged blast, what fraction of MCL-1 is in the mitochondrial matrix rather than the outer membrane, and does that ratio predict response to MCL1 inhibition or to the BCL-2/MCL1 co-inhibition now proposed for infant KMT2A-rearranged ALL? A submitochondrial fractionation on two or three lines would answer it.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
MCL-1 promotes survival and confers therapeutic resistance in AML, particularly in high-risk subtypes harbouring KMT2A rearrangements; inhibition of electron transport chain complex I is a synthetic lethal partner for MCL-1 inhibition, with synergistic loss of viability in AML cell lines and PDX samples in vitro and significantly prolonged survival in PDX-bearing mice; mechanistically complex I inhibition activates the integrated stress response, producing ATF4 activation downstream of the eIF2-alpha kinase HRI, and HRI activation is dependent on the mitochondrial stress messenger DELE1.
Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia. · Brakefield-Laird L, Budhraja A, Hall PM, ..., Opferman JT · Cell Death Dis 2026What this evidence cannot show
Abstract read this session. **This is an AML study whose abstract frames KMT2A-rearranged AML as the motivating high-risk subtype and as the population that may benefit, not as the tested genotype.** The abstract does not state how many of the cell lines or PDX samples are KMT2A-rearranged, nor report a KMT2A-stratified analysis, so it must not be recorded as a KMT2A-selective result. The brief that dispatched this beat asked whether this paper is KMT2A-specific: on the abstract, it is KMT2A-motivated and AML-general. Myeloid only; no lymphoid or infant data.
Evidence that argues against this (1)
- Complex I inhibition is the manoeuvre that creates the MCL-1 dependency here, and in MLL-rearranged B-ALL inhibiting oxidative phosphorylation blunts blast proliferation while promoting the emergence of leukaemia-initiating cells. The same intervention that opens this therapeutic window in myeloid disease may open a relapse route in lymphoid disease. Morris V et al. 2022
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Gene expression profiling identified high-level MCL-1 expression as associated with prednisolone resistance in MLL-rearranged infant ALL; qRT-PCR in a cohort of MLL-rearranged infant ALL and paediatric non-infant ALL samples confirmed the in vitro association, MCL-1 expression was significantly higher in MLL-rearranged infant patients with a poor in vivo prednisone response than in good responders, and RNA-interference knockdown of MCL-1 in prednisolone-resistant MLL-rearranged cells led, to some extent, to prednisolone sensitisation; the authors state that high MCL-1 is not the sole resistance mechanism.
Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL-rearranged infant acute lymphoblastic leukemia. · Stam RW, Den Boer ML, Schneider P, ..., Pieters R · Blood 2010What this evidence cannot show
Abstract read this session. 2010 expression-array-era study; cohort sizes are not given in the abstract and no correction for multiple testing is described there. The resensitisation is explicitly partial ('to some extent'), and the authors themselves state MCL-1 is not the sole mechanism - an unusually clear self-limitation that should be preserved whenever this paper is cited. The association is with prednisone/prednisolone response, a prognostic surrogate in this disease, not directly with survival. The same association is reported in more favourable childhood ALL subtypes, so it is not KMT2A-specific.
Evidence that argues against this (1)
- In the 2026 preclinical study of MCL1 inhibition in this exact population, sensitivity to the MCL1 inhibitor S63845 did NOT correlate with MCL-2 family protein or mRNA levels including MCL1; BCL-XL mRNA correlated positively with IC50 and KMT2A-rearranged cells had lower BCL-XL protein. High MCL-1 expression therefore does not predict response to MCL-1 inhibition in the same disease in which it predicts steroid resistance. Karsa M et al. 2026
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In preclinical models of infant KMT2A-rearranged ALL, S63845 sensitivity did not correlate with BCL-2 family protein levels; BCL-XL mRNA correlated positively with S63845 IC50; dosing S63845 twice weekly at 12.5 mg/kg or higher combined with venetoclax induced lethal tumour lysis syndrome in 67% of treated mice (8/12) with histopathological debris accumulation in kidney and lung, whereas tumour lysis syndrome was not observed with either monotherapy or with concurrent dexamethasone.
BCL-2 and MCL1 co-inhibition enhances glucocorticoid therapy in preclinical models of infant KMT2A-rearranged acute lymphoblastic leukaemia. · Karsa M, Karsa A, Spurling D, ..., Somers K · Br J Haematol 2026What this evidence cannot show
Full text read this session from Europe PMC (PMC13461956, body present, 46,433 characters after tag-stripping); the PubMed record returns an empty abstract, so anything sourced from the abstract alone would be empty rather than wrong. The tumour lysis figures are from a small murine experiment (12 mice) and TLS in NOD/SCID mice bearing high-burden ALL xenografts is not straightforwardly translatable. Separately, this paper's introduction asserts that MCL1 is a direct target gene of KMT2A fusion proteins and cites for it a paper about a BCL-2 specific enhancer (Godfrey et al. 2017); that specific assertion should not be propagated from here.
Evidence that argues against this (1)
- A first-in-human study of a different MCL-1 inhibitor in relapsed/refractory haematological malignancies reported a low overall response rate with a high incidence of laboratory troponin elevation, so the strong preclinical combination activity has not so far translated for this class in patients. Desai P et al. 2024
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
MIK665, a BH3 mimetic targeting MCL1, was effective as a single agent against a diverse panel of AML cell lines and showed significant activity against a subset of paediatric AML patient-derived xenografts ex vivo and in vivo, with minimal impact on cardiac tissue pathophysiology in that study.
The myeloid cell leukaemia-1 inhibitor MIK665 is a potent therapy in preclinical models of paediatric acute myeloid leukaemia. · Connerty P, Colgan JN, El-Najjar F, ..., Lock RB · Br J Haematol 2026What this evidence cannot show
Abstract read this session. Paediatric AML generally; the abstract names no KMT2A subgroup, so this is not KMT2A evidence. 'A subset of PDX' is not quantified in the abstract, and a subset response without a stated biomarker is a weak translational signal. The cardiac claim is a mouse histopathology observation and is directly contradicted, as a class matter, by human troponin data from two other MCL-1 inhibitors - a mouse heart is a poor model for this specific toxicity.
Evidence that argues against this (1)
- A selective MCL-1 inhibitor produced increases in plasma cardiac troponin in 4 of 8 patients in a first-in-human study without other corresponding cardiac findings, and the authors conclude that treatment-induced troponin release is a consequence of MCL-1 inhibition and may represent a class effect in human patients. Yuda J et al. 2023
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
CRISPR drop-out screening in AML cells identified the genes encoding the proapoptotic regulators BAK and NOXA as hits conferring resistance to mebendazole-induced MYB degradation; conversely, targeting MCL1 with a BH3-mimetic significantly enhanced the anti-AML activity of mebendazole in AML cell lines in vitro and in paediatric PDX AML cells ex vivo, and the combination impaired disease progression in mice transplanted with THP-1 AML cells or aggressive infant PDX AML cells.
MCL1 inhibition to enhance the efficacy of MYB targeting in pediatric acute myeloid leukemia. · Tsakaneli A, Che N, Virely C, ..., Williams O · Cell Death Dis 2026What this evidence cannot show
Abstract read this session. THP-1 is a KMT2A::MLLT3 line and the abstract mentions infant PDX AML cells, so KMT2A-rearranged material is plausibly included, but the abstract makes no genotype-stratified claim and the study is framed as paediatric AML. Mebendazole is an anti-helminth with many cellular activities; attributing the combination effect specifically to MYB degradation rests on the earlier work, not on this abstract.
Evidence that argues against this (1)
- The same group's parallel work shows that in vivo MCL1 inhibition in paediatric leukaemia models delivers little as a single agent and that combinations carry dose-limiting on-target toxicity, so a preclinical combination benefit does not establish a usable therapeutic index. Karsa M et al. 2026
- E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
In a phase 1 first-in-human study of AZD5991 (monotherapy n=61; combination with venetoclax n=17), four deaths occurred due to adverse events of which only tumour lysis syndrome was related to AZD5991; three patients with myelodysplastic syndrome achieved an objective response; asymptomatic elevations of troponin I or T were observed in 8 (10.3%) patients, and a post hoc analysis found elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any dose at or after cycle 1; the authors conclude treatment was associated with a high incidence of laboratory troponin elevation and a low overall response rate.
A Phase 1 First-in-Human Study of the MCL-1 Inhibitor AZD5991 in Patients with Relapsed/Refractory Hematologic Malignancies. · Desai P, Lonial S, Cashen A, ..., Blachly JS · Clin Cancer Res 2024What this evidence cannot show
Abstract read this session. Adult relapsed/refractory haematological malignancies; no paediatric or infant data and no KMT2A-rearranged subgroup is reported in the abstract. The troponin finding is complicated by the post hoc observation that many patients had elevated troponin T before any dose, which the authors report and which weakens a simple drug-attribution reading. A low response rate in heavily pretreated adults does not establish that the target is wrong in a chemo-naive infant.
Evidence that argues against this (1)
- Preclinical infant KMT2A-rearranged ALL models show that MCL1 inhibition is effective only in a triple combination with venetoclax and dexamethasone, not as monotherapy; a monotherapy-dominated phase 1 is therefore a weak test of the hypothesis that MCL1 matters in this disease. Karsa M et al. 2026
- E7established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt reviewed human record Q07820 (MCL1_HUMAN) has primary gene name MCL1, gene synonym BCL2L3, length 350 aa, and recommended protein name 'Induced myeloid leukemia cell differentiation protein Mcl-1'.
UniProtKB entry Q07820 (MCL1_HUMAN), Induced myeloid leukemia cell differentiation protein Mcl-1 · UniProt Consortium · UniProt 2026What this evidence cannot show
Resolved 2026-09-20 with gene_exact:MCL1 AND organism_id:9606 AND reviewed:true; exactly one reviewed row and gene_primary read back as MCL1. Note the synonym BCL2L3: the BCL-2 family is dense with L-numbered paralogues (BCL2L1/BCL-XL 233 aa, BCL2L11/BIM, BCL2L2/BCL-W) and this graph's literature routinely uses protein rather than gene names, so match on the primary symbol. MCL1 at 350 aa and BCL2L1 at 233 aa are well separated by length, which makes the length assertion a real defence here.
Evidence that argues against this (1)
- A database record cannot settle the question that matters for this entry, which is whether MCL1 is a direct transcriptional target of the KMT2A fusion. The assertion circulating in the recent literature traces to a citation about a BCL-2 enhancer, so the direct-target claim remains unestablished in this graph. Stam RW et al. 2010
- E_q65_loc1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
MCL-1 occupies two separable mitochondrial compartments encoded by one gene: an outer-mitochondrial-membrane form that antagonises apoptosis like other anti-apoptotic BCL-2 proteins, and an amino-terminally truncated form imported into the mitochondrial MATRIX that is necessary for mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure and maintenance of oligomeric ATP synthase.
Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. · Perciavalle RM, et al. · Nat Cell Biol 2012;14:575-83 2012What this evidence cannot show
Non-leukaemic cell systems; nothing here was done in a KMT2A-rearranged or infant B-lineage cell (brief rule 73). This is a ONE-GENE, ONE-ACCESSION, TWO-COMPARTMENT case of the same class the registry logs for CDK9 42k/55k: accession Q07820 plus length 350 aa gives zero protection against a claim attached to the wrong pool. Read from the fetched abstract.
Evidence that argues against this (1)
- Whether the matrix form is generated at the outer membrane or inside the matrix was contested in the same period, and the N-terminal processing step that defines the matrix pool is not settled; a localisation-blind MCL1 inhibitor's effect cannot be assigned to one pool on this evidence. Germain M et al. 2007
- E_q65_loc2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
A minor nuclear pool of MCL-1 localises to sites of DNA damage and regulates the DNA damage response - the only nuclear localisation of MCL-1 found in any source read for this beat.
MCL-1 localizes to sites of DNA damage and regulates DNA damage response. · Jamil S, et al. · Cell Cycle 2010;9:2843-55 2010What this evidence cannot show
Damage-induced foci are a state, not a compartment, and the paper names no nuclear body. Not done in leukaemia. Abstract only.
Evidence that argues against this (1)
- The dominant and best-evidenced MCL-1 pools are submitochondrial; promoting a damage-induced nuclear focus to a subnuclear address would mispredict what MCL-1 inhibition does to a cell. Perciavalle RM et al. 2012
- E_q65_loc3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In preclinical models of infant KMT2A-rearranged acute lymphoblastic leukaemia - the index disease of this graph - BCL-2 and MCL1 co-inhibition enhances glucocorticoid therapy; this is the closest MCL1 work to the index disease and it carries no localisation measurement.
BCL-2 and MCL1 co-inhibition enhances glucocorticoid therapy in preclinical models of infant KMT2A-rearranged acute lymphoblastic leukaemia. · Karsa M, et al. · Br J Haematol 2026;209:786-792 2026What this evidence cannot show
Cited here only to bound the absence: it establishes that MCL1 is studied in the right disease and that its compartment is not. PubMed returns an EMPTY abstract for this record, so the claim is restricted to what the title asserts; the paper is open access as PMC13461956 and was not read in full for this beat.
Evidence that argues against this (1)
- A drug-combination result is not evidence about where the protein is. MCL-1's matrix pool has a respiratory function distinct from its apoptotic one, so an MCL1 inhibitor's effect in this disease need not act through the compartment the rationale assumes. Perciavalle RM et al. 2012
A COMPETING RESISTANCE ROUTE: high MCL-1 tracks prednisolone resistance independently of receptor level.
- confers resistance to →Prednisolone - the active steroid, the drug every resistance experiment in this disease actually used, and the one given into the spinal fluid
high MCL-1 associated with in-vitro prednisolone resistance and in-vivo prednisone poor response in MLL-rearranged infant ALL
gene-level entry for the target that combination addresses
high MCL-1 associated with poor in vivo prednisone response in MLL-rearranged infant ALL
complex I inhibition creates the MCL-1 dependency via DELE1-HRI-ATF4
- co-occurs with →BCL2 — the one co-dependency in this beat that already has an approved drug pointed at it
BCL-2 and MCL1 co-inhibition is the combination that works in infant KMT2A-r ALL models
MCL1 sets the second axis of apoptotic priming alongside BCL-2
on-target cardiomyocyte consequence of MCL-1 inhibition
- co-occurs with →Venetoclax in KMT2A-rearranged leukemia — the apoptotic partner every other drug needs
MCL1-inhibitor plus venetoclax doublet caused lethal tumour lysis in 8/12 mice
MCL-1 dependence is created by complex I inhibition, linking it to the OXPHOS state
complex I inhibition manufactures the MCL-1 dependency via DELE1-HRI-ATF4
on-target cardiac biomarker signal reported for two structurally distinct MCL-1 inhibitors
MCL-1 is the graph's third mitochondrial-pool record and the only one split between outer membrane and matrix from a single gene
- related to →BCL2 — the one co-dependency in this beat that already has an approved drug pointed at it
BCL2 is the graph's outer-membrane case; MCL-1 occupies that membrane AND a second matrix compartment BCL2 does not, so co-inhibition is not a symmetric perturbation
pharmacological cardiac signal in humans rather than a demonstrated cardiomyocyte requirement: selective MCL-1 inhibition raised plasma troponin with no other cardiac findings, and whether that is reversible permeabilisation or cell loss is unresolved