Inhibition of the anti-apoptotic protein MCL-1 severely suppresses human hematopoiesis

Bohler, Sheila; Afreen, Sehar; Fernández‐Orth, Juncal; Demmerath, Eva-Maria; Molnár, Christian; Wu, Ying; Weiss, Julia Miriam; Mittapalli, Venugopal R.; Konstantinidis, Lukas; Schmal, Hagen; Kunze, Mirjam; Erlacher, Miriam

doi:10.3324/haematol.2020.252130

Cited by 20 publications

(8 citation statements)

References 51 publications

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“…As both MCL-1 and Bcl-XL inhibitors are currently progressing through clinical trials to treat different malignancies, our results suggest possible harmful effect on the most primitive HSPCs, especially when given in this combination and in conjunction with DNA-damaging therapies. These results corroborate previous reports highlighting the importance of MCL1 and Bcl-XL in HSPC survival 62–65 .…”

Section: Discussionsupporting

confidence: 93%

“…Combined inhibition of MCL-1 and BCL-XL using their respective inhibitors prevented MSC-mediated protection of irradiated HSPCs, strongly nominating these proteins as critical mediators of HSPCs survival in the niche context. Our findings extend the observations of Bohler and colleagues, who reported synthetic lethality between MCL-1 and Bcl-xL inhibitors on human CD34+ cells 62 . As both MCL-1 and Bcl-XL inhibitors are currently progressing through clinical trials to treat different malignancies, our results suggest possible harmful effect on the most primitive HSPCs, especially when given in this combination and in conjunction with DNA-damaging therapies.…”

Section: Discussionsupporting

confidence: 92%

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Mesenchymal Stromal Cells regulate human Hematopoietic Stem Cell survival and regeneration via cAMP/PKA pathway

Muddineni,

Even,

Zipin-Roitman

et al. 2023

Preprint

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Ionizing radiation and chemotherapy suppress normal Hematopoietic Stem and Progenitor Cells (HSPCs) function and present an inherent risk of developing bone marrow failure and secondary leukemias. Mesenchymal Stromal Cells (MSCs) constitute an essential HSPC niche component by regulating HSPC quiescence, self-renewal, survival, and differentiation. Yet, the underlying pro-regenerative signaling pathways activated in HSPCs by MSCs remain poorly understood. Here, using co-culture system of bone marrow-derived MSCs and HSPCs we established that irradiated HSPCs co-cultured with MSCs underwent significantly less apoptosis and maintained theirin vivorepopulating ability. We reveal that MSCs mediate protection by preserving pro-survival MCL1 protein levels in human HSPCs. Moreover, using unbiased HSPC transcriptomic analysis complemented with ex vivo and in vivo validation studies we discovered that MSCs activate cAMP/PKA/CREB signaling pathway in HSPCs to prevent MCL1 decline and apoptosis onset upon irradiation. Pharmacological activation of cAMP signaling pathway in human HSPCs replicated MSC mediated protection of HSPC functionality. Collectively, our results highlight the role of cAMP/PKA/CREB signaling pathway in MSC-HSPC cross-talk and its critical role in the regulation of survival and self-renewal ability of human HSPCs. Furthermore, we also revealed pharmacological agents that can mitigate radiation-induced hematological sequelae.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Mesenchymal Stromal Cells regulate human Hematopoietic Stem Cell survival and regeneration via cAMP/PKA pathway

Muddineni,

Even,

Zipin-Roitman

et al. 2023

Preprint

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“…Although the Bcl-2 and Mcl-1 inhibitor combination was tolerated in mice, 84 toxicities for this combination in humans cannot be ruled out. 84,85 Our data in supplemental Figure 7 highlight this possibility. We find that the combination of venetoclax with pevonedistat, bortezomib, or MI-2 is selectively toxic to multidrug-resistant CLL cells (Figure 5B-D).…”

Section: Discussionmentioning

confidence: 79%

Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL

et al. 2021

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The Bcl-2 inhibitor venetoclax (VEN) has yielded exceptional clinical responses in chronic lymphocytic leukemia (CLL). However, de novo resistance can result in failure to achieve negative minimal residual disease and predicts poor treatment outcomes. Consequently, additional pro-apoptotic drugs, such as inhibitors of Mcl-1 and Bcl-xL, are in development. By profiling anti-apoptotic proteins using flow cytometry, we find that leukemic B-cells recently emigrated from the lymph node (LN) (CD69Pos/CXCR4Low) in vivo are enriched for cell clusters simultaneously overexpressing multiple anti-apoptotic proteins (Mcl-1high/Bcl-xLhigh/Bcl-2high), in both treated and treatment naïve CLL patients. These cells exhibited anti-apoptotic resistance to multiple BH-domain antagonists, including inhibitors of Bcl-2, Mcl-1, and Bcl-xL, when tested as single agents in a flow cytometry-based functional assay. Anti-apoptotic multi-drug resistance declines ex vivo, consistent with resistance being generated in vivo by extrinsic microenvironmental interactions. Surviving "persister" cells in patients undergoing venetoclax treatment are enriched for CLL cells displaying the functional and molecular properties of microenvironmentally-induced multi-drug resistance. Overcoming this resistance required simultaneous inhibition of multiple anti-apoptotic proteins, with potential for unwanted toxicities. Using a drug screen performed using patient PBMCs cultured in an ex vivo microenvironment model we identify novel venetoclax drug combinations that induce selective cytotoxicity in multi-drug resistant CLL cells. Thus, we demonstrate that anti-apoptotic multi-drug resistant CLL cells exist in patients de novo, and show that these cells persist during pro-apoptotic treatment such as venetoclax. We validate clinically actionable approaches to selectively deplete this reservoir in patients.

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“…In a report on multiple myeloma (MM), experiments showed that knocking down Mcl-1 can significantly enhance the sensitivity of MM cells to ABT-199 [31]. Although many studies aim to combine Bcl-2 mimetics with Mcl-1 specific mimetics, it is believed that simultaneously inhibit Bcl-2 and Mcl-1 may bring obvious side effect, since both of them involved in a number of important physiological functions [32,33]. Therefore, there is an urgent need to find a combination plan for reversing the compensatory increase of other anti-apoptotic protein after venetoclax exposure.…”

Section: Ivyspringmentioning

confidence: 99%

Metformin exerts a synergistic effect with venetoclax by downregulating Mcl-1 protein in acute myeloid leukemia

Zhou¹,

Zeng²,

Cheng³

et al. 2021

J. Cancer

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Background: Recently, one of the specific BH3-mimetics, Venetoclax has been approved by FDA providing new options for newly diagnosed AML patient especially who are unfitted to receive conventional chemotherapy. Though the clinical success of venetoclax has been achieved in clinical outcomes such as complete remission (CR) and overall survival. Acquired resistance to ABT-199 which is induced by the regulation of apoptosis pathway is still an important clinical problem. To this end, the attempt to combine drugs which can reverse the compensatory regulation is urgent. Methods: In three AML cell lines (KG-1, Kasumi-1 and THP-1), the anti-AML effects of the combination of and metformin or the two drugs used alone were compared. CCK8 was used to evaluate the cell viability, and flow cytometry was used to estimate the rate of apoptosis, Western blot method was performed to detect apoptosis-related protein levels. In mice experiments, female BALB/c-nu nude mice were subcutaneously injected with THP-1 cells for subcutaneous tumor formation, and the combined effect of ABT-199 and metformin was tested. The evaluation indicators were tumor size, tumor weight, and Ki67 staining. Mouse body weight and HE staining were detected to evaluate liver damage and adverse drug reactions. Results: Both in vitro and in vivo experiments showed that compared with metformin or ABT-199 alone, the combined use of the two drugs exerts a synergistic effect on promoting apoptosis, thereby producing a strong anti-leukemia effect. Furthermore, after a short incubation time, ABT-199 swiftly increased the expression level of the anti-apoptotic protein Mcl-1, while the combined use of metformin and ABT-199 significantly reduced the level of Mcl-1. Notably, Metformin significantly downregulates the level of Mcl-1 protein by inhibiting its protein production. To less extent, metformin can also downregulate the expression of another anti-apoptotic protein, BCL-xl. Conclusion:Metformin downregulates the expression of anti-apoptotic proteins Mcl-1 and Bcl-xl by inhibiting protein production, and shows a synergistic anti-tumor effect with ABT-199 in acute myeloid leukemia.

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Inhibition of the anti-apoptotic protein MCL-1 severely suppresses human hematopoiesis

Cited by 20 publications

References 51 publications

Mesenchymal Stromal Cells regulate human Hematopoietic Stem Cell survival and regeneration via cAMP/PKA pathway

Mesenchymal Stromal Cells regulate human Hematopoietic Stem Cell survival and regeneration via cAMP/PKA pathway

Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL

Metformin exerts a synergistic effect with venetoclax by downregulating Mcl-1 protein in acute myeloid leukemia

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