The clinical mutatome of core binding factor leukemia

Opatz, Sabrina; Bamopoulos, Stefanos A.; Metzeler, Klaus H.; Herold, Tobias; Ksienzyk, Bianka; Bräundl, Kathrin; Tschuri, Sebastian; Vosberg, Sebastian; Konstandin, Nikola P.; Wang, Christine; Hartmann, Luise; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Schneider, Stephanie; Thiede, Christian; Middeke, Jan Moritz; Stölzel, Friedrich; Röllig, Christoph; Schetelig, Johannes; Ehninger, Gerhard; Krämer, Alwin; Braess, Jan; Görlich, Dennis; Sauerland, Maria Cristina; Berdel, Wolfgang E.; Wörmann, Bernhard; Hiddemann, Wolfgang; Spiekermann, Karsten; Bohlander, Stefan K.; Greif, Philipp A.

doi:10.1038/s41375-019-0697-0

Cited by 59 publications

(60 citation statements)

References 41 publications

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“…Previous studies have shown that some of them were associated with AML. CBFB forms fusion genes CBFB/MYH11, which block differentiation in AML [24], but the deletion of CBFB usually was accompanied with the deletion of MYH11, and the deletion of MYH11/CBFB had no negative effect on the prognosis [25]. Our ndings suggested deletion-induced downregulating CBFB expression has positive effects on the prognosis.…”

Section: Discussionmentioning

confidence: 60%

Identification of Prognostic Signature Based on the Copy Number Variation (CNV) and Expression in Acute Myeloid Leukemia

Niu¹,

Wu²,

Li³

et al. 2020

Preprint

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Purpose Acute myeloid leukemia (AML) is caused by multiple genetic alterations in the hematopoietic progenitors, and molecular genetic analysis has provided useful information for AML diagnosis and prognosis. However, an integrative understanding about the prognosis value of specific copy number variation (CNV) and CNV-modulated gene expression has been limited. Methods We conducted an integrative analysis of CNV profiling and gene expression using data from the TARGET and TCGA AML cohorts. The CNV data from TCGA were analyzed using the GISTIC. CNV survival analysis and mRNA survival analysis were conducted with the Multivariate Cox proportional hazards regression model using R software with “survminer” and “survival” packages. KEGG cancer panel genes were extracted from the cancer related pathways from Kyoto Encyclopedia of Genes and Genomes (KEGG). The R package “circlize” was used for mapping the CNV genes to chromosomes. Results From this investigation, we observed distinct CNV patterns in the AML risk groups as well as the expression of 251 genes significantly modulated by CNV in both cohorts. There were 102 CNV genes (located at 7q31-34, 16q24) associated with clinical outcomes in AML, which were identified in the TARGET cohort and validated in the TCGA cohort, three of which being miRNA genes (MIR29A, MIR183, MIR335) that overlapped with a KEGG cancer panel. Five genes were identified whose expressions were modulated by CNV and significantly associated with clinical outcomes, and among them, the deletion of SEMA4D and CBFB were found to potentially have protective effects against AML. Moreover, the distribution of CNV in these five CNV-modulated genes was independent of the risk groups, which suggests that they are independent prognosis factors. Conclusion Overall, this study identified 102 CNV genes and five CNV-modulated gene expressions that are crucial for developing new modes of prognosis evaluation and target therapy for AML.

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Section: Discussionmentioning

confidence: 60%

Identification of Prognostic Signature Based on the Copy Number Variation (CNV) and Expression in Acute Myeloid Leukemia

Niu¹,

Wu²,

Li³

et al. 2020

Preprint

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“…The most puzzling fact about ZBTB7A mutations in AML is their exclusive presence in the context of core binding factor leukemia, mainly in t(8;21) AML [1][2][3][4][5][6], which suggests a specific collaboration between RUNX1-RUNX1T1 and loss of ZBTB7A function. Of note, it was previously reported that RUNX1-RUNX1T1 causes a block of the monocytic and erythrocytic linages in favor of granulocytic differentiation in mouse and zebrafish [9,23].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we and others found the transcription factor ZBTB7A mutated in acute myeloid leukemia (AML) with translocation t (8;21), at frequencies ranging from 9.4 to 23% [1][2][3][4][5][6]. Hotspot mutations result either in loss (A175fs) or alteration (R402) of the C-terminal zinc finger domain, which is critical for DNA-binding of ZBTB7A [1].…”

Section: Introductionmentioning

confidence: 99%

ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells

et al. 2020

Self Cite

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ZBTB7A is frequently mutated in acute myeloid leukemia (AML) with t(8;21) translocation. However, the oncogenic collaboration between mutated ZBTB7A and the RUNX1-RUNX1T1 fusion gene in AML t(8;21) remains unclear. Here, we investigate the role of ZBTB7A and its mutations in the context of normal and malignant hematopoiesis. We demonstrate that clinically relevant ZBTB7A mutations in AML t(8;21) lead to loss of function and result in perturbed myeloid differentiation with block of the granulocytic lineage in favor of monocytic commitment. In addition, loss of ZBTB7A increases glycolysis and hence sensitizes leukemic blasts to metabolic inhibition with 2-deoxy-D-glucose. We observed that ectopic expression of wild-type ZBTB7A prevents RUNX1-RUNX1T1-mediated clonal expansion of human CD34+ cells, whereas the outgrowth of progenitors is enabled by ZBTB7A mutation. Finally, ZBTB7A expression in t(8;21) cells lead to a cell cycle arrest that could be mimicked by inhibition of glycolysis. Our findings suggest that loss of ZBTB7A may facilitate the onset of AML t(8;21), and that RUNX1-RUNX1T1-rearranged leukemia might be treated with glycolytic inhibitors.

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“…Acute promyelocytic leukemia HERC1-PML genomic fusion [9] Acute Myeloid Leukemia HERC1 mutations [10] Acute lymphoblastic leukemia Decreased MSH2 protein levels and HERC1 deletions [11] Adult T-cell acute lymphoblastic leukemia HERC1 mutations [12] T-cell prolymphocytic leukemia HERC1 mutations [13] Non-melanoma skin cancer Enhanced BAK protein degradation [14] Pulmonary sclerosing pneumocytoma HERC1 mutations [15] Invasive lobular breast cancer HERC1 mutations [16] Metastatic triple-negative breast cancer HERC1 mutations [17] Sporadic colorectal cancer Decreased MSH2 protein levels and HERC1 deletions [11] Osteosarcoma Negative correlation of SOX18 overexpression and HERC1 mRNA levels [18]…”

Section: Herc1mentioning

confidence: 99%

“…Negative correlation of CCL20 overexpression and HERC5 mRNA levels [46] Reduced p53, p21 and Bax/Bcl-2 pathway activation [47] Ovarian cancer HERC5 upregulation is associated with drug resistance [48,49] Osteosarcoma Negative correlation of SOX18 overexpression and HERC5 mRNA levels [18] HERC6 Osteosarcoma Negative correlation of SOX18 overexpression and HERC6 mRNA levels [18] Mutations in large HERCs have been found in leukemia [10][11][12][13] and breast cancer [16,17]. Frameshift mutations in HERC2 have been found in both gastric and colorectal carcinomas with microsatellite instability [31].…”

Section: Herc2mentioning

confidence: 99%

HERC Ubiquitin Ligases in Cancer

Sala-Gaston

Martinez-Martinez

Pedrazza

et al. 2020

Cancers

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HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3–HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies.

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The clinical mutatome of core binding factor leukemia

Cited by 59 publications

References 41 publications

Identification of Prognostic Signature Based on the Copy Number Variation (CNV) and Expression in Acute Myeloid Leukemia

Identification of Prognostic Signature Based on the Copy Number Variation (CNV) and Expression in Acute Myeloid Leukemia

ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells

HERC Ubiquitin Ligases in Cancer

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