Similar Datasets
Project description:Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukemia (AML), upon progression or relapsed/refractory disease1-6. Here, by employing synthetic leukemogenesis in human cells, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors, GMPs) harboring previously acquired driver mutations, revealing that advanced leukemic clones originate from a different cell type than more ancestral clones. Furthermore, we demonstrate that RAS-mutant leukemia stem cells (LSCs) give rise to monocytic disease, as frequently observed in patients with poor responses to treatment with the BCL2 inhibitor drug Venetoclax (VEN). We show that this is because RAS-mutant LSCs, in contrast to RAS-WT LSCs, have altered BCL2 family gene expression profiles and are resistant to VEN, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver by imposing a specific LSC target cell restriction shapes the non-genetic cellular hierarchy of AML and critically impacts therapeutic outcomes in patients.
2024-09-10 | GSE275501 | GEO
Project description:Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukemia (AML), upon progression or relapsed/refractory disease1-6. Here, by employing synthetic leukemogenesis in human cells, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors, GMPs) harboring previously acquired driver mutations, revealing that advanced leukemic clones originate from a different cell type than more ancestral clones. Furthermore, we demonstrate that RAS-mutant leukemia stem cells (LSCs) give rise to monocytic disease, as frequently observed in patients with poor responses to treatment with the BCL2 inhibitor drug Venetoclax (VEN). We show that this is because RAS-mutant LSCs, in contrast to RAS-WT LSCs, have altered BCL2 family gene expression profiles and are resistant to VEN, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver by imposing a specific LSC target cell restriction shapes the non-genetic cellular hierarchy of AML and critically impacts therapeutic outcomes in patients.
2024-08-09 | GSE253702 | GEO
Project description:Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukemia (AML), upon progression or relapsed/refractory disease1-6. Here, by employing synthetic leukemogenesis in human cells, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors, GMPs) harboring previously acquired driver mutations, revealing that advanced leukemic clones originate from a different cell type than more ancestral clones. Furthermore, we demonstrate that RAS-mutant leukemia stem cells (LSCs) give rise to monocytic disease, as frequently observed in patients with poor responses to treatment with the BCL2 inhibitor drug Venetoclax (VEN). We show that this is because RAS-mutant LSCs, in contrast to RAS-WT LSCs, have altered BCL2 family gene expression profiles and are resistant to VEN, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver by imposing a specific LSC target cell restriction shapes the non-genetic cellular hierarchy of AML and critically impacts therapeutic outcomes in patients.
2024-08-09 | GSE253696 | GEO
Project description:Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukemia (AML), upon progression or relapsed/refractory disease1-6. Here, by employing synthetic leukemogenesis in human cells, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors, GMPs) harboring previously acquired driver mutations, revealing that advanced leukemic clones originate from a different cell type than more ancestral clones. Furthermore, we demonstrate that RAS-mutant leukemia stem cells (LSCs) give rise to monocytic disease, as frequently observed in patients with poor responses to treatment with the BCL2 inhibitor drug Venetoclax (VEN). We show that this is because RAS-mutant LSCs, in contrast to RAS-WT LSCs, have altered BCL2 family gene expression profiles and are resistant to VEN, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver by imposing a specific LSC target cell restriction shapes the non-genetic cellular hierarchy of AML and critically impacts therapeutic outcomes in patients.
2024-08-09 | GSE253426 | GEO
Project description:Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukemia (AML), upon progression or relapsed/refractory disease1-6. Here, by employing synthetic leukemogenesis in human cells, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors, GMPs) harboring previously acquired driver mutations, revealing that advanced leukemic clones originate from a different cell type than more ancestral clones. Furthermore, we demonstrate that RAS-mutant leukemia stem cells (LSCs) give rise to monocytic disease, as frequently observed in patients with poor responses to treatment with the BCL2 inhibitor drug Venetoclax (VEN). We show that this is because RAS-mutant LSCs, in contrast to RAS-WT LSCs, have altered BCL2 family gene expression profiles and are resistant to VEN, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver by imposing a specific LSC target cell restriction shapes the non-genetic cellular hierarchy of AML and critically impacts therapeutic outcomes in patients.
2024-08-09 | GSE254478 | GEO
Project description:Venetoclax (VEN) has transformed the therapy of acute myeloid leukemia (AML), but resistance and relapse are a major challenge. Monocytic differentiation was proposed as a cause of VEN resistance, but clinical and laboratory evidence is conflicting. Here we harness AML patientderived induced pluripotent stem cells (iPSCs) and Genotyping of Transcriptomes (GoT) to interrogate how mutational status and differentiation stage affect VEN sensitivity independently of one another. Findings in primary and iPSC-derived AML stem cells (LSCs) and monocytic blasts, together with clinical trial data, reveal that monocytic blasts are resistant to VEN, in contrast to LSCs, which express high levels of BCL2 and are sensitive, and that it is the latter, but not the former, that determines the clinical outcome. Crucially, N/KRAS-mutant LSCs produce more monocytic blasts, downregulate BCL2 and are resistant to VEN, driving clinical resistance or relapse. We thus provide a unifying mechanistic model of VEN resistance in AML.
2024-08-09 | GSE235206 | GEO
Project description:BH3 mimetics are used as an efficient strategy to promote mitochondrial-dependent cell death in blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML, while various compounds targeting MCL1 are in clinical trials. Yet, drug resistance eventually ensues, highlighting the urgency to understand the underlying mechanisms. Our genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy regulators sensitizes AML to BH3 mimetics. One such regulator is Mitofusin-2 (MFN2), a GTPase that controls mitochondrial dynamics and the degradation of damaged mitochondria through mitophagy. Resistance to BH3 mimetics is accompanied by alterations in mitochondrial morphology, enhanced mitochondria-endoplasmic reticulum interactions, and augmented mitophagy flux. MFN2 inactivation, using a novel small molecule inhibitor, and pharmacologic inhibition of mitophagy synergizes with BH3 mimetics. Overall, targeting of mitophagy along with BCL2-family members is a promising strategy to overcome drug resistance in AML.
2023-07-10 | GSE182401 | GEO
Project description:Overexpression of Mcl-1 is implicated in resistance of several cancers to chemotherapeutic treatment, therefore identifying a safe way to decrease its expression in tumor cells represents a central goal. We investigated if a modulation of the diet could impact on Mcl-1 expression using a Myc-driven lymphoma model. We established that a partial reduction of caloric intake by 25% represents an efficient way to decrease Mcl-1 expression in tumor cells. Furthermore, using isocaloric custom diets, we observed that carbohydrates (CHO) are the main regulators of Mcl-1 expression within the food. Indeed, feeding lymphoma-bearing mice with a diet having 25% less carbohydrates was sufficient to decrease Mcl-1 expression by 50% in lymphoma cells. We showed that a low CHO diet resulted in AMPK activation and mTOR inhibition leading to eukaryotic elongation factor 2 (eEF2) inhibition, blocking protein translation elongation. Strikingly, a low CHO diet was sufficient to sensitize Myc-driven lymphoma-bearing mice to ABT-737-induced cell death in vivo. Thus reducing carbohydrate intake may represent a safe way to decrease Mcl-1 expression and to sensitize tumor cells to anti-cancer therapeutics.
| S-EPMC5341978 | biostudies-literature
Project description:Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the TP53 tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action-direct targeting of mitochondria independently of TP53 gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs.
| S-EPMC8466478 | biostudies-literature
Project description:Despite advances in the treatment of acute myeloid leukemia (AML), prognosis of AML patients is still dismal and better treatment options are required. B-cell Lymphoma 2 (BCL-2) homology domain 3 (BH3)-mimetics are emerging as a novel class of apoptosis-inducing agents that are currently being tested for the treatment of different hematological malignancies including AML. Particularly, the selective BCL-2 inhibitor ABT-199/Venetoclax is demonstrating clinical responses and has recently been approved in combination for the treatment of AML. Compounds targeting the related protein MCL-1 have recently entered clinical trials, highlighting the urgency to compare the different BH3-mimetics and identify the most promising antiapoptotic target in AML. We performed a side-by-side comparison of different highly selective and potent BH3-mimetics targeting BCL-2 (ABT-199), MCL-1 (S63845) or BCL-xL (A1331852) in a panel of AML cell lines and primary patient cells. Gene knockdown using siRNAs was utilized to investigate the functional relevance of BCL-2 proteins. Western blotting and immunoprecipitations were used to explore the influence of BH3-mimetics on interactions between pro- and antiapoptotic BCL-2 proteins. A1331852 induced apoptosis only in selected cases, indicating that BCL-xL is not a very promising therapeutic target in AML. However, S63845 displayed higher potency than ABT-199, with more cell lines and primary cells responding to S63845 than to ABT-199. MCL-1 dependency in AML cells was confirmed by siRNA-mediated knockdown of MCL-1, which was sufficient to induce apoptosis. S63845-induced cell death was accompanied by a displacement of the BH3-only protein BIM as well as BAK, resulting in BAK-dependent apoptosis. In contrast, ABT-199-induced cell death was mediated by BAX rather than BAK, indicating distinct non-redundant molecular functions of BCL-2 and MCL-1 in AML. Our study reveals that MCL-1 may be a more prevalent therapeutic target than BCL-2 in AML and identifies BIM and BAK as important mediators of S63845-induced apoptosis in AML.
| S-EPMC6892884 | biostudies-literature