Differential Gene Expression Patterns and Interaction Networks in BCR/ABL Positive and Negative Adult Acute Lymphoblastic Leukemias.

Juric, Dejan; Lacayo, Norman J.; Ramsey, Meghan; Racevskis, Janis; Wiernik, Peter H.; Rowe, Jacob M.; Goldstone, Anthony H.; O’Dwyer, Peter J.; Paietta, Elisabeth; Šikić, Branimir I.

doi:10.1182/blood.v108.11.1836.1836

Cited by 20 publications

(25 citation statements)

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“…In breast cancer, FYN expression was shown to correlate with poorer survival, and correlated with FAK up‐regulation [17]. In haematological malignancies, FYN has been identified as a putative target for treating BCR‐ABL‐expressing adult acute lymphoblastic leukaemia, due to the centrality of its relationship to several important molecular signals suspected to drive the proliferation of malignant leukaemic blasts [18] Compounds active against FYN have shown in vitro antiproliferative activity in acute lymphoblastic leukaemia [19]. In other solid tumours such as melanoma, FYN has been implicated as a mediator of integrin signalling, and thus appears to regulate metastatic potential [20].…”

Section: Discussionmentioning

confidence: 99%

FYN is overexpressed in human prostate cancer

Posadas¹,

Al‐Ahmadie²,

Robinson³

et al. 2008

BJU International

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analysis, we described FYN expression in prostate cancer. The analysis included 32 cases of prostate cancer, nine of prostatic intraepithelial neoplasia (PIN) and 19 normal prostates. Samples were scored for the percentage of stained glands and intensity of staining (from 0 to 3). Each sample was assigned a composite score generated by multiplying percentage and intensity. RESULTSData-mining showed an eight times greater FYN expression in prostate cancer than in normal tissue; this was specific to FYN and not present for other SFKs. Expression of FYN in prostate cancer cell lines (LNCaP, 22Rv1, PC3, DuPro) was detected using quantitative RT-PCR and immunoblotting. Expression of FYN and its signalling partners FAK and PXN was detected in human tissue. Comparing normal with cancer samples, there was a 2.1-fold increase in median composite score for FYN ( P < 0.001) 1.7-fold increase in FAK ( P < 0.001), and a doubling in PXN ( P < 0.05). There was a 1.7-fold increase in FYN ( P < 0.05) and a 1.6-fold increase in FAK ( P < 0.01) in cancer compared with PIN. CONCLUSIONSThese studies support the hypothesis that FYN and its related signalling partners are up-regulated in prostate cancer, and support further investigation into the role of the FYN as a therapeutic target. OBJECTIVETo test the hypothesis that FYN , a member of the SRC family of kinases (SFKs), is up-regulated in prostate cancer, as FYN is functionally distinct from other SFKs, and interacts with FAK and paxillin (PXN), regulators of cell morphology and motility.

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Section: Discussionmentioning

confidence: 99%

FYN is overexpressed in human prostate cancer

Posadas¹,

Al‐Ahmadie²,

Robinson³

et al. 2008

BJU International

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“…These two probesets, located at the 3 0 -end of IZKF1 were selected as they manifested the highest mRNA signals compared to other IKZF1 probesets, as expected due to oligo(dT) primers utilized in the reverse transcription step to obtain cDNA. Of the fourteen IKZF1 IK-Deletions (14) Normal (32) Up-regulated ( Supplementary Table SII). Expression Analysis Systematic Explorer (EASE) score negative-log-transformed values are used, with higher values represent more significantly over-represented categories.…”

Section: Patients With Ikzf1 Deletions Form a Distinct Subset Of Pedimentioning

confidence: 99%

Ikaros deletions in BCR-ABL-negative childhood acute lymphoblastic leukemia are associated with a distinct gene expression signature but do not result in intrinsic chemoresistance

Vitanza

Zaky

Blum

et al. 2014

Pediatr Blood Cancer

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Background Ikaros, the product of IKZF1, is a regulator of lymphoid development and polymorphisms in the gene have been associated with the childhood acute lymphoblastic leukemia (ALL). Additionally, IKZF1 deletions and mutations identify high risk biological subsets of ALL [1, 2]. Procedure To discover the underlying pathways modulated by Ikaros we performed gene expression and gene ontology analysis in IKZF1 deleted primary B-ALL pediatric patient samples. To validate downstream targets we performed qPCR on individual patient samples. We also created IKZF1 knockdown B-ALL cell lines with over 50% reduction of Ikaros, mimicking haplosufficient Ikaros deletions, and again performed qPCR to investigate the downstream targets. Finally, to understand the association of Ikaros deletion with a poor prognosis we challenged our IKZF1 knockdown cell lines with chemotherapy and compared responses to IKZF1 wild-type controls. Results We report a specific gene expression signature of 735 up-regulated and 473 down-regulated genes in IKZF1 deleted primary B-ALL pediatric patient samples. Gene ontology studies revealed an up-regulation of genes associated with cell adhesion, cytoskeletal regulation, and motility in IKZF deleted patient samples. Validated up-regulated target genes in IKZF1 deleted patient samples included CTNND1 and PVRL2 (p=0.0003 and p=0.001), and RAB3IP and SPIB (p=0.005 and p=0.032) were down-regulated. In further studies in IKZF1 knockdown cell lines, apoptosis assays showed no significant chemoresistance. Conclusion IKZF1 knockdown alone does not impart intrinsic chemotherapy resistance suggesting that the association with a poor prognosis may be due to additional lesions, microenvironmental interactions with the bone marrow niche, or other factors.

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“…23 PRL-3 overexpression is also seen in hematopoietic malignancies, including acute lymphoblastic leukemia and multiple myeloma. 24,25 In addition, PRL-3 is involved in leukemogenesis of chronic myeloid leukemia as a downstream target of BCR-ABL signaling pathway. 26 Besides, PRL-3 protein is upregulated in 47% of AML cases with internal tandem duplication of FLT3 (FLT3-ITD), as a downstream effector of FLT3-ITD to confer therapeutic resistance through upregulation of STAT and antiapoptotic Mcl-1 protein, 27 or by FLT3-ITD-STAT5 signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Independent oncogenic and therapeutic significance of phosphatase PRL‐3 in FLT3‐ITD–negative acute myeloid leukemia

Liu

Guo

et al. 2014

Cancer

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BACKGROUNDInternal tandem duplication of FMS-like tyrosine kinase (FLT3-ITD) is well known to be involved in acute myeloid leukemia (AML) progression, but FLT3-ITD–negative AML cases account for 70% to 80% of AML, and the mechanisms underlying their pathology remain unclear. This study identifies protein tyrosine phophatase PRL-3 as a key mediator of FLT3-ITD–negative AML.METHODSA total of 112 FLT3-ITD–negative AML patients were sampled between 2010 and 2013, and the occurrence of PRL-3 hyperexpression in FLT3-ITD–negative AML was evaluated by multivariate probit regression analysis. Overexpression or depletion of endogenous PRL-3 expression with the specific small interfering RNAs was performed to investigate the role of PRL-3 in AML progression. Xenograft models were also used to confirm the oncogenic role of PRL-3.RESULTSCompared to healthy donors, PRL-3 is upregulated more than 3-fold in 40.2% of FLT3-ITD–negative AML patients. PRL-3 expression level is adversely correlated to the overall survival of the AML patients, and the AML relapses accompany with re-upregulation of PRL-3. Mechanistically, aberrant PRL-3 expression promoted cell cycle progression and enhanced the antiapoptotic machinery of AML cells to drug cytotoxicity through downregulation of p21 and upregulation of Cyclin D1 and CDK2 and activation of STAT5 and AKT. Depletion of endogenous PRL-3 sensitizes AML cells to therapeutic drugs, concomitant with apoptosis by upregulation of cleaved PARP (poly ADP ribose polymerase) and apoptosis-related caspases. Xenograft assays further confirmed PRL-3’s oncogenic role in leukemogenesis.CONCLUSIONSOur results demonstrated that PRL-3 is a novel independent crucial player in both FLT3-ITD–positive and FLT3-ITD–negative AML and could be a potential therapeutic target. Cancer 2014;120:2130–2141. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.FLT3-ITD–negative acute myeloid leukemia (AML) accounts for up to approximately 70% to 80% of all cases. This study demonstrates that PRL-3, an independent driver in FLT3-ITD–negative AML, is adversely correlated to patient survival. Mechanistically, PRL-3 can promote AML cell cycle progression and render antiapoptosis features to AML cells, suggesting it could be an independent factor for AML diagnosis and therapy.

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Differential Gene Expression Patterns and Interaction Networks in BCR/ABL Positive and Negative Adult Acute Lymphoblastic Leukemias.

Cited by 20 publications

References 0 publications

FYN is overexpressed in human prostate cancer

FYN is overexpressed in human prostate cancer

Ikaros deletions in BCR-ABL-negative childhood acute lymphoblastic leukemia are associated with a distinct gene expression signature but do not result in intrinsic chemoresistance

Independent oncogenic and therapeutic significance of phosphatase PRL‐3 in FLT3‐ITD–negative acute myeloid leukemia

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