The Mitochondrial Carrier Homolog 2 (MTCH2) Regulates the Differentiation of AML Cells By Influencing the Localization of Pyruvate Dehydrogenase Complex and H3 and H4 Histone Acetylation
Bibliographic record
Abstract
Abstract Mitochondrial carrier homolog 2 (MTCH2) is a mitochondrial outer membrane protein that functions as a receptor-like protein for pro-apoptotic BID. In addition to its role in apoptosis, recent findings show that MTCH2 also regulates cellular metabolism. In murine hematopoietic cells, loss of MTCH2 increases oxidative phosphorylation and reduces the number of hematopoietic stem cells. Here, we sought to understand the role of MTCH2 in leukemogenesis and knocked down MTCH2 in leukemia cell lines using multiple independent shRNAs. Knockdown of MTCH2 reduced growth and viability of AML cells: OCI-AML2 (>90%), TEX (>80%), U937 (>65%), and HL60 (>75%). MTCH2 knockdown also decreased the clonogenic growth of OCI-AML2 (>60%), TEX (>70%), and U937 (>40%) cells compared to controls. However, MTCH2 knockdown did not induce cell death as indicated by annexin V/PI staining. In addition, knockdown of MTCH2 in TEX cells reduced engraftment into the marrow of non-obese diabetic/severe combined immunodeficiency-growth factor (NOD/SCID-GF) mice (control 17±4%, n=10) vs. sh-MTCH2 (4±0.86%, n=10). In mouse models, knockout of MTCH2 decreased the leukomogenic potential of murine hematopoietic stem cells transformed with the MLL-AF9 oncogene and increased the survival of these mice. To understand the mechanism by which MTCH2 knockdown decreased cell growth, we used genome wide transcriptome analysis with RNA-seq and observed an up regulation of genes involved in cellular differentiation. Consistent with increased MTCH2 knockdown promoting differentiation, OCI-AML2 cells with MTCH2 knockdown displayed increased non-specific esterase staining. Increased differentiation (Lin+ve cells) was also observed in MLL-AF9 with MTCH2 knockout. Knockdown of MTCH2 in TEX and OCI-AML2 cells increased levels of H3 and H4 histone acetylation as demonstrated by immunoblotting. Of note, differentiation and increased H3 and H4 acetylation was not observed after inhibiting other mitochondrial processes, such as mitochondrial protein synthesis or mitochondrial DNA replication. Although MTCH2 is a receptor for BID, the increased H3 and H4 acetylation appeared independent of BID as small molecule BID inhibitors did not alter H3 and H4 acetylation. MTCH2 regulates cell metabolism. Therefore, we measured changes in intracellular metabolites in AML cells after MTCH2 knockdown. In AML cells, MTCH2 knockdown increased levels of lactate (2 fold), but did not change the basal rate of oxygen consumption or the activity of mitochondrial respiratory chain complexes. Loss of mitochondrial pyruvate dehydrogenase complex increases lactate levels and a recent study reported that the translocation of pyruvate dehydrogenase complex from the mitochondria to the nucleus under conditions of mitochondrial stress, increases H3 and H4 histone acetylation (Cell. 2014; 158(1):84-97). Therefore, we measured changes in the localization of pyruvate dehydrogenase complex after MTCH2 knockdown. Knockdown of MTCH2 decreased mitochondrial and increased nuclear dehydrogenase complex in OCI-AML2 and TEX cells. Thus, in summary, MTCH2 regulates the differentiation of AML cells and controls the localization of pyruvate dehydrogenase complex and histone acetylation. These results also suggest a mechanism by which loss of MTCH2 leads to reductions of normal hematopoietic stem cells. Disclosures Schimmer: Novartis: Honoraria.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".