OVEREXPRESSION OF PTP4A3 IN ETV6-RUNX1 ACUTE LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Grönroos T. 06/09/16; 132398; E849
Toni Grönroos
Contributions
Contributions
Abstract
Abstract: E849
Type: Eposter Presentation
Background
Acute leukemia is the most common cancer in childhood. The ETV6-RUNX1 (E/R) fusion gene is present in 25 % of childhood precursor B cell acute lymphoblastic leukemia (pB-ALL). E/R fusion is acquired in utero by a translocation between chromosomes 12 and 21 (t[12,21][p13;q22]). Translocation creates an aberrant fusion transcription factor which induces genome-wide repression of regulatory sequences and gene transcripts. The family of protein tyrosine phosphatase 4A (PTP4A) proteins are phosphatases with dual specificity. The family consists of three closely related members (PTP4A1-3) and they participate in a wide range of cellular activities, including cell proliferation, migration and invasion. Kinases and phosphatases have an intricate relationship in balancing intracellular signalling activity, and this balance is often deregulated in malignancies.
Aims
There are indications that members of the PTP4A family are involved in pathogenesis of various hematological malignancies. This motivated us to investigate the role of PTP4A3 in acute lymphoblastic leukemias by using gene expression data on patient samples, bioinformatic analyses and experimental manipulation of cell lines.
Methods
We investigated expression of members of PTP4A family across acute and chronic leukemias, cell lines and healthy cells of hematopoietic origin in a large collection of patient samples assayed by Affymetrix HU2.0 microarray and retrieved from GEO database. After normalization and manual curation, a two-dimensional “leukemia-map” was generated by t-SNE to visualize the data. We used experimental manipulation of cell lines to validate our findings from the “leukemia-map”.
Results
PTP4A3 showed markedly increased expression among pre-B-ALL and decreased expression in acute myeloid leukemias, chronic leukemias and healthy cells. In further scrutiny, strong expression of PTP4A3 coincided with the E/R subtype of pB-ALL, showing approximately four-fold higher expression as compared to other pB-ALL leukemias (p = 5.449805e-50). To validate the finding, two more patient data sets were retrieved to confirm the higher expression of PTP4A3 in the E/R subtype. In agreement, induction of E/R fusion in Nalm-6 cells increased the level of PTP4A3 mRNA. At primary transcript level, as assayed by global nuclear run-on sequencing (GRO-seq), the decrease of PTP4A3 expression after E/R knockdown was evident. Further, we identified a number of potential E/R binding sites upstream of PTP4A3 gene. Inhibition of PTP4A3 phosphatase activity in E/R positive REH cells was better tolerated as compared to other tested ALL cells.
Conclusion
We show that expression of PTP4A3 is markedly upregulated in the E/R subtype of acute pB-ALL. Our data hint that PTP4A3 expression is regulated by the E/R fusion itself, suggesting further studies on the surrounding regulatory elements. The potential role of PTP4A3 inhibitors will be further evaluated in combination with the known anti-leukemic drugs.
Session topic: E-poster
Keyword(s): ETV6, Leukemia, RUNX1
Type: Eposter Presentation
Background
Acute leukemia is the most common cancer in childhood. The ETV6-RUNX1 (E/R) fusion gene is present in 25 % of childhood precursor B cell acute lymphoblastic leukemia (pB-ALL). E/R fusion is acquired in utero by a translocation between chromosomes 12 and 21 (t[12,21][p13;q22]). Translocation creates an aberrant fusion transcription factor which induces genome-wide repression of regulatory sequences and gene transcripts. The family of protein tyrosine phosphatase 4A (PTP4A) proteins are phosphatases with dual specificity. The family consists of three closely related members (PTP4A1-3) and they participate in a wide range of cellular activities, including cell proliferation, migration and invasion. Kinases and phosphatases have an intricate relationship in balancing intracellular signalling activity, and this balance is often deregulated in malignancies.
Aims
There are indications that members of the PTP4A family are involved in pathogenesis of various hematological malignancies. This motivated us to investigate the role of PTP4A3 in acute lymphoblastic leukemias by using gene expression data on patient samples, bioinformatic analyses and experimental manipulation of cell lines.
Methods
We investigated expression of members of PTP4A family across acute and chronic leukemias, cell lines and healthy cells of hematopoietic origin in a large collection of patient samples assayed by Affymetrix HU2.0 microarray and retrieved from GEO database. After normalization and manual curation, a two-dimensional “leukemia-map” was generated by t-SNE to visualize the data. We used experimental manipulation of cell lines to validate our findings from the “leukemia-map”.
Results
PTP4A3 showed markedly increased expression among pre-B-ALL and decreased expression in acute myeloid leukemias, chronic leukemias and healthy cells. In further scrutiny, strong expression of PTP4A3 coincided with the E/R subtype of pB-ALL, showing approximately four-fold higher expression as compared to other pB-ALL leukemias (p = 5.449805e-50). To validate the finding, two more patient data sets were retrieved to confirm the higher expression of PTP4A3 in the E/R subtype. In agreement, induction of E/R fusion in Nalm-6 cells increased the level of PTP4A3 mRNA. At primary transcript level, as assayed by global nuclear run-on sequencing (GRO-seq), the decrease of PTP4A3 expression after E/R knockdown was evident. Further, we identified a number of potential E/R binding sites upstream of PTP4A3 gene. Inhibition of PTP4A3 phosphatase activity in E/R positive REH cells was better tolerated as compared to other tested ALL cells.
Conclusion
We show that expression of PTP4A3 is markedly upregulated in the E/R subtype of acute pB-ALL. Our data hint that PTP4A3 expression is regulated by the E/R fusion itself, suggesting further studies on the surrounding regulatory elements. The potential role of PTP4A3 inhibitors will be further evaluated in combination with the known anti-leukemic drugs.
Session topic: E-poster
Keyword(s): ETV6, Leukemia, RUNX1
Abstract: E849
Type: Eposter Presentation
Background
Acute leukemia is the most common cancer in childhood. The ETV6-RUNX1 (E/R) fusion gene is present in 25 % of childhood precursor B cell acute lymphoblastic leukemia (pB-ALL). E/R fusion is acquired in utero by a translocation between chromosomes 12 and 21 (t[12,21][p13;q22]). Translocation creates an aberrant fusion transcription factor which induces genome-wide repression of regulatory sequences and gene transcripts. The family of protein tyrosine phosphatase 4A (PTP4A) proteins are phosphatases with dual specificity. The family consists of three closely related members (PTP4A1-3) and they participate in a wide range of cellular activities, including cell proliferation, migration and invasion. Kinases and phosphatases have an intricate relationship in balancing intracellular signalling activity, and this balance is often deregulated in malignancies.
Aims
There are indications that members of the PTP4A family are involved in pathogenesis of various hematological malignancies. This motivated us to investigate the role of PTP4A3 in acute lymphoblastic leukemias by using gene expression data on patient samples, bioinformatic analyses and experimental manipulation of cell lines.
Methods
We investigated expression of members of PTP4A family across acute and chronic leukemias, cell lines and healthy cells of hematopoietic origin in a large collection of patient samples assayed by Affymetrix HU2.0 microarray and retrieved from GEO database. After normalization and manual curation, a two-dimensional “leukemia-map” was generated by t-SNE to visualize the data. We used experimental manipulation of cell lines to validate our findings from the “leukemia-map”.
Results
PTP4A3 showed markedly increased expression among pre-B-ALL and decreased expression in acute myeloid leukemias, chronic leukemias and healthy cells. In further scrutiny, strong expression of PTP4A3 coincided with the E/R subtype of pB-ALL, showing approximately four-fold higher expression as compared to other pB-ALL leukemias (p = 5.449805e-50). To validate the finding, two more patient data sets were retrieved to confirm the higher expression of PTP4A3 in the E/R subtype. In agreement, induction of E/R fusion in Nalm-6 cells increased the level of PTP4A3 mRNA. At primary transcript level, as assayed by global nuclear run-on sequencing (GRO-seq), the decrease of PTP4A3 expression after E/R knockdown was evident. Further, we identified a number of potential E/R binding sites upstream of PTP4A3 gene. Inhibition of PTP4A3 phosphatase activity in E/R positive REH cells was better tolerated as compared to other tested ALL cells.
Conclusion
We show that expression of PTP4A3 is markedly upregulated in the E/R subtype of acute pB-ALL. Our data hint that PTP4A3 expression is regulated by the E/R fusion itself, suggesting further studies on the surrounding regulatory elements. The potential role of PTP4A3 inhibitors will be further evaluated in combination with the known anti-leukemic drugs.
Session topic: E-poster
Keyword(s): ETV6, Leukemia, RUNX1
Type: Eposter Presentation
Background
Acute leukemia is the most common cancer in childhood. The ETV6-RUNX1 (E/R) fusion gene is present in 25 % of childhood precursor B cell acute lymphoblastic leukemia (pB-ALL). E/R fusion is acquired in utero by a translocation between chromosomes 12 and 21 (t[12,21][p13;q22]). Translocation creates an aberrant fusion transcription factor which induces genome-wide repression of regulatory sequences and gene transcripts. The family of protein tyrosine phosphatase 4A (PTP4A) proteins are phosphatases with dual specificity. The family consists of three closely related members (PTP4A1-3) and they participate in a wide range of cellular activities, including cell proliferation, migration and invasion. Kinases and phosphatases have an intricate relationship in balancing intracellular signalling activity, and this balance is often deregulated in malignancies.
Aims
There are indications that members of the PTP4A family are involved in pathogenesis of various hematological malignancies. This motivated us to investigate the role of PTP4A3 in acute lymphoblastic leukemias by using gene expression data on patient samples, bioinformatic analyses and experimental manipulation of cell lines.
Methods
We investigated expression of members of PTP4A family across acute and chronic leukemias, cell lines and healthy cells of hematopoietic origin in a large collection of patient samples assayed by Affymetrix HU2.0 microarray and retrieved from GEO database. After normalization and manual curation, a two-dimensional “leukemia-map” was generated by t-SNE to visualize the data. We used experimental manipulation of cell lines to validate our findings from the “leukemia-map”.
Results
PTP4A3 showed markedly increased expression among pre-B-ALL and decreased expression in acute myeloid leukemias, chronic leukemias and healthy cells. In further scrutiny, strong expression of PTP4A3 coincided with the E/R subtype of pB-ALL, showing approximately four-fold higher expression as compared to other pB-ALL leukemias (p = 5.449805e-50). To validate the finding, two more patient data sets were retrieved to confirm the higher expression of PTP4A3 in the E/R subtype. In agreement, induction of E/R fusion in Nalm-6 cells increased the level of PTP4A3 mRNA. At primary transcript level, as assayed by global nuclear run-on sequencing (GRO-seq), the decrease of PTP4A3 expression after E/R knockdown was evident. Further, we identified a number of potential E/R binding sites upstream of PTP4A3 gene. Inhibition of PTP4A3 phosphatase activity in E/R positive REH cells was better tolerated as compared to other tested ALL cells.
Conclusion
We show that expression of PTP4A3 is markedly upregulated in the E/R subtype of acute pB-ALL. Our data hint that PTP4A3 expression is regulated by the E/R fusion itself, suggesting further studies on the surrounding regulatory elements. The potential role of PTP4A3 inhibitors will be further evaluated in combination with the known anti-leukemic drugs.
Session topic: E-poster
Keyword(s): ETV6, Leukemia, RUNX1
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