Genomic analysis of acute leukemia

Mullighan, Charles G.

doi:10.1111/j.1751-553x.2009.01167.x

Cited by 20 publications

(11 citation statements)

References 117 publications

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“…[43][44][45] In summary, this study revealed an essential role for the Mef2c/d proteins in regulating transition through the first checkpoint in early development by integrating the MAPK signals of the pre-BCR to a downstream transcriptional network, thereby controlling proliferation and orchestrating the progression through the next phase of B-cell development. In view of growing recognition that disruption of pre-BCR controls can lead to leukemia, 75,76 this work provides insight into the mechanism by which MEF2C and MEF2D disruption [23][24][25] contributes to acute lymphoblastic leukemia.…”

Section: Discussionmentioning

confidence: 99%

Essential control of early B-cell development by Mef2 transcription factors

Herglotz¹,

Unrau²,

Hauschildt³

et al. 2016

Blood

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Key Points• Mef2c and Mef2d are activated by the pre-B-cell receptor and are essential for pre-B-cell transition.• Mef2c complexes with B-cell transcription factors to shut down the immediate early response and to initiate a new transcriptional network.The sequential activation of distinct developmental gene networks governs the ultimate identity of a cell, but the mechanisms involved in initiating downstream programs are incompletely understood. The pre-B-cell receptor (pre-BCR) is an important checkpoint of B-cell development and is essential for a pre-B cell to traverse into an immature B cell. Here, we show that activation of myocyte enhancer factor 2 (Mef2) transcription factors (TFs) by the pre-BCR is necessary for initiating the subsequent genetic network. We demonstrate that B-cell development is blocked at the pre-B-cell stage in mice deficient for Mef2c and Mef2d TFs and that pre-BCR signaling enhances the transcriptional activity of Mef2c/d through phosphorylation by the Erk5 mitogen-activating kinase. This activation is instrumental in inducing Krüppel-like factor 2 and several immediate early genes of the AP1 and Egr family. Finally, we show that Mef2 proteins cooperate with the products of their target genes (Irf4 and Egr2) to induce secondary waves of transcriptional regulation. Our findings uncover a novel role for Mef2c/d in coordinating the transcriptional network that promotes early B-cell development. (Blood. 2016;127(5):572-581)

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Section: Discussionmentioning

confidence: 99%

Essential control of early B-cell development by Mef2 transcription factors

Herglotz¹,

Unrau²,

Hauschildt³

et al. 2016

Blood

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“…To investigate small copy number changes in a genomewide manner array-based comparative genome hybridization (aCGH) can be applied (SolinasToldo et al, 1997;Albertson and Pinkel, 2003;Fiegler et al, 2003). In childhood acute lymphoblastic leukemia, this approach has led to the identification of alterations in genes like PAX5 or IKAROS, previously not implicated in the pathogenesis of the disease (Mullighan, 2009). One major advantage of applying aCGH to the analysis of MDS, a disease characterized by enhanced levels of apoptosis and often by a hypocellular marrow (Clark and Lampert, 1990;Niemeyer et al, 1992;Kerbauy and Deeg, 2007), is that no dividing cells are needed.…”

Section: Introductionmentioning

confidence: 99%

Clonal heterogeneity in childhood myelodysplastic syndromes—Challenge for the detection of chromosomal imbalances by array‐CGH

Praulich

Tauscher

Göhring

et al. 2010

Genes Chromosomes & Cancer

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To evaluate whether copy number alterations (CNAs) are present that may contribute to disease development and/or progression of childhood myelodysplastic syndromes (MDS), 36 pediatric MDS patients were analyzed using array-based comparative genome hybridization (aCGH). In addition to monosomy 7, the most frequent chromosome aberration in childhood MDS, novel recurrent CNAs were detected. They included a loss of 3p14.3-p12.3, which contains the putative tumor suppressor gene FHIT, a loss of 7p21.3-p15.3, a loss of 9q33.3-q34.3 (D184) and microdeletions in 17p11.2, 6q23 containing MYB, and 17p13 containing TP53. In this small patient cohort, patients without CNA, patients with monosomy 7 only and patients with one CNA in addition to monosomy 7 did not differ in their survival. As expected, all patients with complex karyotypes, including two patients with deletions of TP53, died. A challenge inherent to aCGH analysis of MDS is the low percentage of tumor cells. We evaluated several approaches to overcome this limitation. Genomic profiles from isolated granulocytes were of higher quality than those from bone marrow mononuclear cells. Decreased breakpoint calling stringency increased recognition of CNAs present in small clonal populations. However, further analysis using a custom-designed array showed that these CNAs often did not confirm the findings from 244k arrays. In contrast, constitutional CNVs were reliably detected on both arrays. Moreover, aCGH on amplified DNA from distinct myeloid clusters is a new approach to determine CNAs in small subpopulations. Our results clearly emphasize the need to verify array-CGH results by independent methods like FISH or quantitative PCR.

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“…This technique can be used to introduce or correct disease phenotypes such as β‐thalassemia or Alzheimer disease in induced pluripotent stem cell (iPSC) …”

Section: A Future Perspective: Crispr Therapy?mentioning

confidence: 99%

New biomarkers and therapeutic strategies in acute lymphoblastic leukemias: Recent advances

Simioni

Bergamini

Ferioli

et al. 2019

Hematological Oncology

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Acute lymphoblastic leukemia (ALL) represents a heterogeneous group of hematologic malignancies, and it is normally characterized by an aberrant proliferation of immature lymphoid cells. Moreover, dysregulation of multiple signaling pathways that normally regulate cellular transcription, growth, translation, and proliferation is frequently encountered in this malignancy. ALL is the most frequent tumor in childhood, and adult ALL patients still correlate with poor survival. This review focuses on modern therapies in ALL that move beyond standard chemotherapy, with a particular emphasis on immunotherapeutic approaches as new treatment strategies. Bi‐specific T‐cell Engagers (BiTE) antibodies, the chimeric antigen receptor (CAR)‐T cells, or CRISPR‐Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]–associated nuclease 9) represent other new innovative approaches for this disease. Target and tailored therapy could make the difference in previously untreatable cases, i.e., precision and personalized medicine. Clinical trials will help to select the most efficient novel therapies in ALL management and to integrate them with existing treatments to achieve durable cures.

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Genomic analysis of acute leukemia

Cited by 20 publications

References 117 publications

Essential control of early B-cell development by Mef2 transcription factors

Essential control of early B-cell development by Mef2 transcription factors

Clonal heterogeneity in childhood myelodysplastic syndromes—Challenge for the detection of chromosomal imbalances by array‐CGH

New biomarkers and therapeutic strategies in acute lymphoblastic leukemias: Recent advances

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