<i>Ebf1</i> or <i>Pax5</i> haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia

Heltemes-Harris, Lynn; Willette, Mark; Ramsey, Laura B.; Qiu, Yi Hua; Neeley, E. Shannon; Zhang, Nianxiang; Thomas, Deborah A.; Koeuth, Thearith; Baechler, Emily C.; Kornblau, Steven M.; Farrar, Michael A.

doi:10.1084/jem.20101947

Cited by 144 publications

(129 citation statements)

References 77 publications

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“…Interestingly, STAT5 over-activation and PAX5 haplo-insufficiency have been described as synergistic players to initiate ALL [28, 32]. In the present study we demonstrated that both these aberrancies are not only necessary to drive leukemia, but they are a direct consequence of the expression of the PAX5 fusion protein, which can a) repress the activity of endogenous PAX5 [11] and b) activate STAT5 through LCK (Figure 6).…”

Section: Discussionsupporting

confidence: 58%

LCKover-expression drives STAT5 oncogenic signaling inPAX5translocated BCP-ALL patients

et al. 2015

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The PAX5 gene is altered in 30% of BCP-ALL patients and PAX5 chromosomal translocations account for 2–3% of cases. Although PAX5 fusion genes significantly affect the transcription of PAX5 target genes, their role in sustaining leukemia cell survival is poorly understood.In an in vitro model of PAX5/ETV6 leukemia, we demonstrated that Lck hyper-activation, and down-regulation of its negative regulator Csk, lead to STAT5 hyper-activation and consequently to the up-regulation of the downstream effectors, cMyc and Ccnd2. More important, cells from PAX5 translocated patients show LCK up-regulation and over-activation, as well as STAT5 hyper-phosphorylation, compared to PAX5 wt and PAX5 deleted cases. As in BCR/ABL1 positive ALL, the hyper-activation of STAT5 pathway can represent a survival signal in PAX5 translocated cells, alternative to the pre-BCR, which is down-regulated. The LCK inhibitor BIBF1120 selectively reverts this phenomenon both in the murine model and in leukemic primary cells. LCK inhibitor could therefore represent a suitable candidate drug to target this subgroup of ALL patients.

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Section: Discussionsupporting

confidence: 58%

LCKover-expression drives STAT5 oncogenic signaling inPAX5translocated BCP-ALL patients

et al. 2015

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“…EBF1 is essential for normal B cell maturation, and genetic disruption of EBF1 contributes to leukemogenesis 26,27 . A previous study found consistent loss of EBF1 expression in a small CLL cohort 28 .…”

Section: Resultsmentioning

confidence: 99%

DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia

et al. 2016

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Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.

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“…To date, only haploinsufficiency of PAX5 was shown to be important for induction of leukemia in an activated STAT5 B ALL mouse model (80). …”

Section: B Cell All Modelsmentioning

confidence: 99%

Murine Models of Acute Leukemia: Important Tools in Current Pediatric Leukemia Research

2014

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Leukemia remains the most common diagnosis in pediatric oncology and, despite dramatic progress in upfront therapy, is also the most common cause of cancer-related death in children. Much of the initial improvement in outcomes for acute lymphoblastic leukemia (ALL) was due to identification of cytotoxic agents that are active against leukemia followed by the recognition that combination of these cytotoxic agents and prolonged therapy are essential for cure. Recent data demonstrating lack of progress in patients for whom standard chemotherapy fails suggests that the ability to improve outcome for these children will not be dramatically impacted through more intensive or newer cytotoxic agents. Thus, much of the recent research focus has been in the area of improving our understanding of the genetics and the biology of leukemia. Although in vitro studies remain critical, given the complexity of a living system and the increasing recognition of the contribution of leukemia extrinsic factors such as the bone marrow microenvironment, in vivo models have provided important insights. The murine systems that are used can be broadly categorized into syngeneic models in which a murine leukemia can be studied in immunologically intact hosts and xenograft models where human leukemias are studied in highly immunocompromised murine hosts. Both of these systems have limitations such that neither can be used exclusively to study all aspects of leukemia biology and therapeutics for humans. This review will describe the various ALL model systems that have been developed as well as discuss the advantages and disadvantages inherent to these systems that make each particularly suitable for specific types of studies.

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Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia

Abstract: STAT5 is abnormally activated in patients with acute lymphoblastic leukemia, and increased STAT5 activation synergizes with PAX5 and EBF1 to induce disease.

Cited by 144 publications

References 77 publications

LCKover-expression drives STAT5 oncogenic signaling inPAX5translocated BCP-ALL patients

LCKover-expression drives STAT5 oncogenic signaling inPAX5translocated BCP-ALL patients

DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia

Murine Models of Acute Leukemia: Important Tools in Current Pediatric Leukemia Research

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