The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia

Banerji, Versha; Frumm, Stacey M.; Ross, Kenneth N.; Li, Loretta S.; Schinzel, Anna C.; Hahn, Cynthia K.; Kakoza, Rose M.; Chow, Kwan T.; Ross, Linda S.; Alexe, Gabriela; Tolliday, Nicola; Inguilizian, Haig; Galinsky, Ilene; Stone, Richard; DeAngelo, Daniel J.; Roti, Giovanni; Aster, Jon C.; Hahn, William C.; Kung, Andrew L.; Stegmaier, Kimberly

doi:10.1172/jci46465

Cited by 103 publications

(122 citation statements)

References 49 publications

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“…Although the role of GSK-3 in leukemogenesis has been suggested but not clearly explained, the therapeutic potential of GSK-3 inhibitors in acute myeloid leukemia (AML) treatment has already been suggested in several studies. Using a screen based on AML cell lines differentiation, Banerji and colleagues have identified lithium and other GSK-3 inhibitors as possible anti-leukemic agents but the mechanism was not identified (41). A more targeted effect of GSK-3 inhibition was shown in MLL rearranged subtype of AML (20).…”

Section: Discussionmentioning

confidence: 99%

Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent

et al. 2015

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We recently identified that the MEK/ERK1/2 pathway synergized with retinoic acid (RA) to restore both transcriptional activity and RA-induced differentiation in RA-resistant acute promyelocytic leukemia (APL) cells. To target the MEK/ERK pathway, we identified glycogen synthase kinase-3β (GSK-3β) inhibitors including lithium chloride (LiCl) as activators of this pathway in APL cells. Using NB4 (RA-sensitive) and UF-1 (RA-resistant) APL cell lines, we observed that LiCl as well as synthetic GSK-3β inhibitors decreased proliferation, induced apoptosis and restored, in RA-resistant cells, the expression of RA target genes and the RA-induced differentiation. Inhibition of the MEK/ERK1/2 pathway abolished these effects. These results were corroborated in primary APL patient cells and translated in vivo using an APL preclinical mouse model in which LiCl given alone was as efficient as RA in increasing survival of leukemic mice compared with untreated mice. When LiCl was combined with RA, we observed a significant survival advantage compared with mice treated by RA alone. In this work, we demonstrate that LiCl, a well-tolerated agent in humans, has antileukemic activity in APL and that it has the potential to restore RA-induced transcriptional activation and differentiation in RA-resistant APL cells in an MEK/ERK-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent

et al. 2015

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“…shRNA constructs targeting MTH FD2 with miR30 expression cassettes were designed and delivered via a TRM PVIR vector as previously described (Puissant et al, 2014). For virus production, 12 µg of the aforementioned vector with 6 µg pCMV-GAG/POL and pCMV-VSVG (for retroviral infection of human cells) or 6 µg pCMV8.9 and pCMV-VSVG (for lentiviral infection of human or murine cells, respectively) packaging vectors were transfected into the 293 packaging cell line using X-treme-GENE 9 (Roche), and the resulting viral supernatants were harvested as previously described (Banerji et al, 2012). The lentiviral viruses were concentrated using PEG-it Virus Precipitation Solution (SBI Biosciences).…”

Section: Plasmids and Shrna Constructsmentioning

confidence: 99%

“…Cells were lysed in Cell Signaling Lysis Buffer (Cell Signaling Technology), as previously reported (Banerji et al, 2012), and resolved by gel electrophoresis using Novex 4-12% BisTris Gel (Invitrogen), transferred to nitrocellulose membranes (Bio-Rad Laboratories), and blocked for 1 h in 5% BSA (Sigma-Aldrich). Blots were incubated in primary antibody to MTH FD2 (ab56772; Abcam), MYC (5605; Cell Signaling Technology), MTH FD1L (16113-1-AP; Protein Tech), SHMT2 (155230; Abcam), Actin (MS-1295-P; Neomarkers), and Vinculin (ab18058; Abcam), followed by the secondary antibodies anti-rabbit HRP (NA9340V; GE Healthcare) or anti-mouse HRP (NA9310V; GE Healthcare).…”

Section: Immunoblottingmentioning

confidence: 99%

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Targeting MTHFD2 in acute myeloid leukemia

Pikman¹,

Puissant²,

Alexe³

et al. 2016

J Cell Biol

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“…[3][4][5] On the other hand, specific vulnerabilities of AML cells may be revealed by functional studies, such as RNA interference screens or chemical screens. [6][7][8] Letai and colleagues took yet another approach and studied the 'readiness' of AML cells to undergo apoptosis (referred to as "mitochondrial priming") as a way to understand and predict response of AML cells to chemotherapy. 9 Mitochondrial priming is controlled by the BCL2 family of proteins, which contains both pro-apoptotic and anti-apoptotic members.…”

mentioning

confidence: 99%

Primetime for chemotherapy in acute myeloid leukemia

Cools¹

2012

Haematologica

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Hematology News 1775T he basis for the current treatment of acute myeloid leukemia (AML) was developed 40 years ago, and consists of cytarabine (a nucleoside analog) in combination with an anthracycline (DNA intercalating agents and topoisomerase II inhibitors). 1Additional topoisomerase inhibitors are under investigation, and may help to improve the current therapies. 2 Advances in genomic technologies have identified AML as a genetically heterogeneous disease, and many patients can now be categorized into clinicopathological subgroups based on the presence of genetic defects.3-5 On one hand, it is hoped that AML therapy can be improved through individualized treatment strategies based on molecular markers.3-5 On the other hand, specific vulnerabilities of AML cells may be revealed by functional studies, such as RNA interference screens or chemical screens.6-8 Letai and colleagues took yet another approach and studied the 'readiness' of AML cells to undergo apoptosis (referred to as "mitochondrial priming") as a way to understand and predict response of AML cells to chemotherapy. 9Mitochondrial priming is controlled by the BCL2 family of proteins, which contains both pro-apoptotic and anti-apoptotic members. The balance between these proteins determines whether a cell continues to live or activates the cell death program. Several studies have exploited the possibility to measure the 'readiness' of a cell to undergo apoptosis. 10 In practice, this is measured by the release of cytochrome c from mitochondria or the loss of mitochondrial transmembrane potential caused by proapoptotic peptides (BH3 peptides). While all viable cells look 'alive and kicking', mitochondrial priming studies can reveal differences in the cells' vulnerability to inducers of cell death.In a new study, Vo and colleagues observed that mitochondrial priming of AML cell lines correlated closely with sensitivity to topoisomerase II inhibitors, such as etoposide, daunorubicin and mitoxantrone. 9 In contrast, such correlation was not observed for cytarabine, clofarabine, decitabine or azacitidine, suggesting that killing of AML cells is less dependent on mitochondrial priming by these nucleoside analogs and DNA demethylating agents. The authors next studied whether mitochondrial priming of AML blasts at diagnosis could predict the response to therapy. Interestingly, this study revealed a clear correlation between mitochondrial priming and the response of AML patients, making it possible to distinguish patients who obtained complete remission without relapse, complete remission with subsequent relapse, and those who did not obtain complete remission. Furthermore, mitochondrial priming could also further improve the prognostic information provided by molecular markers, such as those of the European LeukemiaNet (ELN).3 These data were also in agreement with a marked difference between mitochondrial priming of sensitive AML blasts and normal hematopoietic stem cells. In contrast, AML blasts from patients who did not respond to treatment had very low...

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The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia

Cited by 103 publications

References 49 publications

Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent

Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent

Targeting MTHFD2 in acute myeloid leukemia

Primetime for chemotherapy in acute myeloid leukemia

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