Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency

Prasad, Mahadesh A. J.; Ungerbäck, Jonas; Åhsberg, Josefine; Somasundaram, Rajesh; Strid, Tobias; Larsson, Malin; Månsson, Robert; Paepe, Annick De; Lilljebjörn, Henrik; Fioretos, Thoas; Hagman, James; Sigvardsson, Mikael

doi:10.1182/blood-2014-12-617282

Cited by 40 publications

(48 citation statements)

References 33 publications

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“…Even though it is possible to identify childhood B-ALL leukemia that , similar to our mouse model, contains combined heterozygous deletion of PAX5 and EBF1 (Mullighan et al 2007;Prasad et al 2015), it is rare in comparison with single-heterozygous mutations in either the PAX5 or EBF1 gene (Mullighan et al 2007;Prasad et al 2015). While we rarely found leukemia development in single-heterozygote mice, a few cases were found among our animals, creating the possibility of exploring whether leukemia cells from single-heterozygote mice display T-lineage plasticity.…”

Section: Ebf1mentioning

confidence: 83%

“…The majority of these mice develops monoclonal or oligoclonal B-lineage leukemias before the age of 30 wk (Supplemental Fig. S1; Prasad et al 2015) that, after transplantation, display a stable phenotype with expansion of leukemic pro-B cells in the bone marrow (BM) and spleens of the recipients . In order to explore whether constitutive activation of Notch signaling, a feature commonly detected in human T-ALL (Weng et al 2004;Lobry et al 2011), would change the phenotype of the leukemia cells, we transduced four independently derived primary pro-B leukemia samples from lymph nodes (LNs) collected from leukemic Pax5…”

Section: Constitutive Activation Of the Notch Signaling Pathway In Prmentioning

confidence: 99%

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Clonal conversion of B lymphoid leukemia reveals cross-lineage transfer of malignant states

et al. 2016

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Even though leukemia is considered to be confined to one specific hematopoietic cell type, cases of acute leukemia of ambiguous lineage and patients relapsing in phenotypically altered disease suggest that a malignant state may be transferred between lineages. Because B-cell leukemia is associated with mutations in transcription factors of importance for stable preservation of lineage identity, we here investigated the potential lineage plasticity of leukemic cells. We report that primary pro-B leukemia cells from mice carrying heterozygous mutations in either or both the Pax5 and Ebf1 genes, commonly mutated in human leukemia, can be converted into T lineage leukemia cells. Even though the conversion process involved global changes in gene expression and lineage-restricted epigenetic reconfiguration, the malignant phenotype of the cells was preserved, enabling them to expand as T lineage leukemia cells in vivo. Furthermore, while the transformed pro-B cells displayed plasticity toward myeloid lineages, the converted cells failed to cause myeloid leukemia after transplantation. These data provide evidence that a malignant phenotype can be transferred between hematopoietic lineages. This has important implications for modern cancer medicine because lineage targeted treatment of leukemia patients can be predicted to provoke the emergence of phenotypically altered subclones, causing clinical relapse.

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Section: Ebf1mentioning

confidence: 83%

Section: Constitutive Activation Of the Notch Signaling Pathway In Prmentioning

confidence: 99%

Clonal conversion of B lymphoid leukemia reveals cross-lineage transfer of malignant states

et al. 2016

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“…Even though the finding that restoration of PAX5 expression in a leukemia model resulted in differentiation of the transformed cells 119 support this idea, a complete block of differentiation as imposed by RAG deficiency, did not result in leukemia formation in collaboration with activated STAT5 as efficiently as heterozygote loss of Pax5 or Ebf1. 118 Furthermore, reduced EBF1 dose result in increased DNA damage in nontransformed B-cell progenitors 116 suggesting that the role of these proteins in the transformation process may be more complex than initially thought.…”

Section: Disruption Of Transcription Factor Network Link Developmentmentioning

confidence: 99%

“…111 Reduced Ebf1 dose as a consequence of a heterozygous mutation of the Ebf1 gene result in reduced numbers of pre-B-cells while the earliest stages of development remain largely unaffected. 111 116 This highlights the sensitivity of regulatory networks in B-lymphocyte development to changes in functional transcription factor dose.…”

Section: Disruption Of Transcription Factor Network Link Developmentmentioning

confidence: 99%

Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia

Somasundaram

Prasad

Ungerbäck

et al. 2015

Blood

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115

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B-lymphocyte development in the bone marrow is controlled by the coordinated action of transcription factors creating regulatory networks ensuring activation of the B-lymphoid program and silencing of alternative cell fates. This process is tightly connected to malignant transformation because B-lineage acute lymphoblastic leukemia cells display a pronounced block in differentiation resulting in the expansion of immature progenitor cells. Over the last few years, high-resolution analysis of genetic changes in leukemia has revealed that several key regulators of normal B-cell development, including IKZF1, TCF3, EBF1, and PAX5, are genetically altered in a large portion of the human B-lineage acute leukemias. This opens the possibility of directly linking the disrupted development as well as aberrant gene expression patterns in leukemic cells to molecular functions of defined transcription factors in normal cell differentiation. This review article focuses on the roles of transcription factors in early B-cell development and their involvement in the formation of human leukemia.

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“…This information is important because antibody-mediated targeting of CLEC-2 may have therapeutic utility as antithrombotic therapy, especially if thrombocytopenia can be avoided. 1 …”

Section: William Plunkett University Of Texas MD Anderson Cancer Centermentioning

confidence: 99%

Arginine addiction in AML

Plunkett

2015

Blood

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Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency

Abstract: Key Points Ebf1 regulates DNA repair in a dose-dependent manner. Combined heterozygote loss of Ebf1 and Pax5 predisposes for leukemia development.

Cited by 40 publications

References 33 publications

Clonal conversion of B lymphoid leukemia reveals cross-lineage transfer of malignant states

Clonal conversion of B lymphoid leukemia reveals cross-lineage transfer of malignant states

Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia

Arginine addiction in AML

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