Gadd45a deficiency accelerates BCR-ABL driven chronic myelogenous leukemia

Mukherjee, Kaushiki; Sha, Xiaojin; Magimaidas, Andrew; Maifrede, Silvia; Skórski, Tomasz; Bhatia, Smita; Hoffman, Barbara; Liebermann, Dan A.

doi:10.18632/oncotarget.14580

Cited by 15 publications

(10 citation statements)

References 40 publications

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“…It is important to note that the human male germ cell line TCam-2 originates from seminoma, which is a type of TGCT [19]. In this context, it is worth noting that almost all NANOS1-repressed pro-apoptotic factors identified in this study (GADD45A, GADD45B, GADD45G, RHOB, and TP53BP2) are well-established tumor suppressors [27][28][29][30][31][32][33][34][35]. This is in line with NANOS1 itself being proposed to promote carcinogenesis [36].…”

Section: Discussionmentioning

confidence: 99%

Human NANOS1 Represses Apoptosis by Downregulating Pro-Apoptotic Genes in the Male Germ Cell Line

Janecki

Ilaslan

Smialek

et al. 2020

IJMS

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While two mouse NANOS paralogues, NANOS2 and NANOS3, are crucial for maintenance of germ cells by suppression of apoptosis, the mouse NANOS1 paralogue does not seem to regulate these processes. Previously, we described a human NANOS1 p.[(Pro34Thr);(Ser83del)] mutation associated with the absence of germ cells in seminiferous tubules of infertile patients, which might suggest an anti-apoptotic role of human NANOS1. In this study, we aimed to determine a potential influence of human NANOS1 on the maintenance of TCam-2 model germ cells by investigating proliferation, cell cycle, and apoptosis. Constructs encoding wild-type or mutated human NANOS1 were used for transfection of TCam-2 cells, in order to investigate the effect of NANOS1 on cell proliferation, which was studied using a colorimetric assay, as well as apoptosis and the cell cycle, which were measured by flow cytometry. RNA-Seq (RNA sequencing) analysis followed by RT-qPCR (reverse transcription and quantitative polymerase chain reaction) was conducted for identifying pro-apoptotic genes repressed by NANOS1. Here, we show that overexpression of NANOS1 downregulates apoptosis in TCam-2 cells. Moreover, we found that NANOS1 represses a set of pro-apoptotic genes at the mRNA level. We also found that the infertility-associated p.[(Pro34Thr);(Ser83del)] mutation causes NANOS1 to functionally switch from being anti-apoptotic to pro-apoptotic in the human male germ cell line. Thus, this report is the first to show an anti-apoptotic role of NANOS1 exerted by negative regulation of mRNAs of pro-apoptotic genes.

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Section: Discussionmentioning

confidence: 99%

Human NANOS1 Represses Apoptosis by Downregulating Pro-Apoptotic Genes in the Male Germ Cell Line

Janecki

Ilaslan

Smialek

et al. 2020

IJMS

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“…Antibody staining was performed on ice for 30 minutes unless specified by the maker. Flow cytometric analysis was carried in a BD FACS Calibur or a BD LSR II flow cytometer as described previously [ 37 ]. Data analysis was performed using FACS Diva (BD Biosciences) or FlowJo software.…”

Section: Methodsmentioning

confidence: 99%

Loss of Egr1, a human del5q gene, accelerates BCR-ABL driven chronic myelogenous leukemia

et al. 2017

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There is substantial evidence that early growth response-1 (Egr1) gene, a zinc-finger transcription factor, behaves as a tumor suppressor in leukemia. This includes reports from this laboratory that constitutive Egr1 overrides leukemia conferred by deregulated c-Myc or E2F-1 in the M1 myeloid leukemic cell line by promoting differentiation. To investigate the effect of Egr1 on the initiation and progression of Chronic Myelogenous Leukemia (CML), lethally irradiated syngeneic wild type mice were reconstituted with bone marrow (BM) from either wild type or Egr1 null mice transduced with a 210-kD BCR-ABL-expressing MSCV-retrovirus (bone marrow transplantation {BMT}). Loss of Egr1 was observed to accelerate the development of BCR-ABL driven leukemia in recipient mice, resulting in the development of a more aggressive disease, a significantly shortened median survival time, and increased BCR-ABL expressing leukemic stem/progenitor cells (GFP+Lin-cKit+Sca+). Egr1 deficient progenitors expressing BCR-ABL exhibited decreased apoptosis, and increased cell viability and proliferation relative to WT counterparts. Secondary BMT of BCR-ABL BM revealed that loss of Egr1 resulted in enrichment of LSCs, consistent with shorter survival time and more aggressive disease of these mice compared to WT counterparts. Furthermore, serial re-plating colony assays indicated that loss of Egr1 increased self-renewal ability of BCR-ABL expressing BM. These novel findings on the tumor suppressor role of Egr1 in CML provide the impetus to study the effect of altering Egr1 expression in AML, where the overall five year survival rate remains low. The effect of loss of Egr1 in CML could reflect its established functions in normal hematopoiesis, maintaining quiescence of HSCs and driving terminal differentiation to the monocyte/macrophage lineage. Gain of function studies should validate these conclusions and provide further rationale for increased Egr1 as a therapeutic target in AML.

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“…BCR-ABL activates multiple signaling pathways including p38MAPK, PI3K/AKT, JNK, STAT5 through its deregulated tyrosine kinase activity to promote proliferation and block differentiation. Our previous study showed that loss of Gadd45a hyperactivated p38MAPK, PI3K/AKT and STAT5 signaling pathways to promote proliferation and reduce apoptosis in BCR-ABL transformed myeloid progenitors [ 14 ]. Thus, it was of interest to determine if the CML suppressive function of Gadd45b is mediated via similar or different signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

“…We have also observed that Gadd45a expression in samples obtained from CML patients was upregulated in more indolent chronic phase CML samples and down regulated in aggressive accelerated phase CML and blast crisis CML [ 14 ]. Thus, studies are underway to determine the expression status of Gadd45b in CML patients.…”

Section: Discussionmentioning

confidence: 99%

Loss of Gadd45b accelerates BCR-ABL-driven CML

2018

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Gadd45b is a member of Gadd45 stress sensor protein family that also includes Gadd45a & Gadd45g. To investigate the effect of Gadd45b in bcr-abl oncogene driven chronic myeloid leukemia (CML) development, syngeneic wild type lethally irradiated mice were reconstituted with either wild type or Gadd45b null myeloid progenitors transduced with a retroviral vector expressing BCR-ABL. Loss of Gadd45b was observed to accelerate BCR-ABL driven CML development with shortened median mouse survival time. BCR-ABL Gadd45b deficient CML progenitors exhibited increased proliferation and decreased apoptosis, associated with hyper-activation of c-Jun NH2-terminal kinase and Stat5. These results provide novel evidence that gadd45b, like gadd45a, functions as a suppressor of BCR-ABL driven leukemia, albeit via a different mechanism.

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Gadd45a deficiency accelerates BCR-ABL driven chronic myelogenous leukemia

Cited by 15 publications

References 40 publications

Human NANOS1 Represses Apoptosis by Downregulating Pro-Apoptotic Genes in the Male Germ Cell Line

Human NANOS1 Represses Apoptosis by Downregulating Pro-Apoptotic Genes in the Male Germ Cell Line

Loss of Egr1, a human del5q gene, accelerates BCR-ABL driven chronic myelogenous leukemia

Loss of Gadd45b accelerates BCR-ABL-driven CML

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