The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells

Mulloy, James C.; Cammenga, Jörg; MacKenzie, Karen L.; Berguido, Francisco J.; Moore, Malcolm A.S.; Nimer, Stephen D.

doi:10.1182/blood.v99.1.15

Cited by 192 publications

(222 citation statements)

References 29 publications

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“…Assays of AML1-ETO function employing either transduction of primary hematopoietic progenitors or inducible transgenic mice have confirmed its role in early multipotent progenitor expansion [4,[23][24][25][26]. This role is more subtle than the differentiation blockade observed in transfected cell lines and argues against a simple unimodal model of transcriptional repression of RUNX1 target genes.…”

Section: Challenges To the Classical Model: Gene Expression Profilesmentioning

confidence: 92%

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Elagib¹,

Goldfarb²

2007

Cancer Letters

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The leukemic fusion protein AML1-ETO occurs frequently in human acute myeloid leukemia (AML) and has received much attention over the past decade. An initial model for its pathogenetic effects emphasized the conversion of a hematopoietic transcriptional activator, RUNX1 (or AML1), into a leukemogenic repressor which blocked myeloid differentiation at the level of target gene regulation. This view has been absorbed into a larger picture of AML1-ETO pathogenesis, encompassing dysregulation of hematopoietic stem cell homeostasis at several mechanistic levels. Recent reports have highlighted a multifaceted capacity of AML1-ETO directly to inhibit key hematopoietic transcription factors that function as tumor suppressors at several nodal points during hematopoietic differentiation. A new model is presented in which AML1-ETO coordinates expansion of the stem cell compartment with diminished lineage commitment and with genome instability.

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Section: Challenges To the Classical Model: Gene Expression Profilesmentioning

confidence: 92%

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Elagib¹,

Goldfarb²

2007

Cancer Letters

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“…[11][12][13] AML1-ETO promotes stem cell renewal and blocks hematopoietic differentiation. [14][15][16] However, its role in blocking cell-cycle progression and promoting apoptosis contradicts its function in promoting leukemogenesis and therefore requires secondary mutagenic events for full transformation. 17,18 We previously identified a single nucleotide insertion that resulted in a truncated AML1-ETO protein (AML1-ETOtr or AEtr), which rapidly promoted leukemia.…”

Section: Introductionmentioning

confidence: 99%

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

Peterson

Yan

et al. 2012

Blood

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IntroductionAcute myeloid leukemia (AML) is a common hematologic malignancy characterized by an abnormal accumulation of myeloid precursors in the bone marrow and blood. Similar to many other types of cancer, genetic abnormalities are associated with the development of AML, particularly chromosomal translocations that result in novel fusion proteins. One of the common translocations implicated in AML is the 8q22;21q22 translocation [t(8;21)]. 1 Based on the French-American-British (FAB) classification of leukemic cells, t(8;21) is associated with nearly 40% of the AML cases with the FAB M2 phenotype. 2 t(8,21) involves the AML1 (RUNX1) gene on chromosome 21 and the ETO (MTG8, RUNX1T1) gene on chromosome 8. [3][4][5] AML1 is the DNA-binding subunit of the core binding factor (CBF) transcription factor complex. Its N-terminus contains a highly conserved DNA binding domain called the runt homology domain (RHD). t(8;21) fuses the N-terminus of AML1 including RHD in-frame with almost the entire ETO protein to form AML1-ETO. [3][4][5][6] This fusion protein acts as a dominant negative form of AML1 during embryogenesis. 7,8 It functions as a transcriptional repressor by interacting with NCoR/SMRT/HDAC. 9,10 AML1-ETO was shown to activate expression of BCL-2 and p21, possibly via interacting with p300. [11][12][13] AML1-ETO promotes stem cell renewal and blocks hematopoietic differentiation. [14][15][16] However, its role in blocking cell-cycle progression and promoting apoptosis contradicts its function in promoting leukemogenesis and therefore requires secondary mutagenic events for full transformation. 17,18 We previously identified a single nucleotide insertion that resulted in a truncated AML1-ETO protein (AML1-ETOtr or AEtr), which rapidly promoted leukemia. 19 Subsequently, we identified a C-terminally truncated variant of AML1-ETO named AML1-ETO9a (AE9a), resulting from alternative splicing and found to coexist with full-length AML1-ETO in most analyzed t(8;21) AML patients. 20 Similar to AEtr, AE9a causes a rapid onset of leukemia in mice, 20 which provides a useful mouse model to study the molecular biology of t(8;21) leukemia.To understand the molecular mechanism of AML1-ETOrelated leukemia development and to explore novel therapeutic targets to treat this type of leukemia, in this study we combined gene expression microarray and promoter occupancy (ChIP-chip) analyses to identify genes directly modulated by AE9a in primary murine leukemia cells. Among the common targets of microarray and ChIP-chip assays, approximately 30% show human t(8;21)-specific up or down-regulation compared with AML that have other chromosomal abnormalities. CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, 21-23 is among those targets. Its expression is down-regulated in AE9a leukemia cells. Consequently, JAK/STAT signaling is enhanced in these leukemia cells. We show that re-expression of CD45 suppresses JAK/STAT activation, delays leukemia development by AE9a an...

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“…For instance, ectopic AML1/MTG8 expression inhibits myeloid differentiation, but also induces apoptosis in leukaemic cell lines such as U937 (Burel et al, 2001). However, AML1/MTG8 supports the expansion of haematopoietic progenitor cells both ex vivo and in vivo by enhancing their self-renewal and, at least in some studies, by interfering with their maturation Rhoades et al, 2000;Mulloy et al, 2002;Tonks et al, 2003;Baesecke et al, 2005). Nevertheless, AML1/MTG8 alone is not sufficient to induce leukaemia in murine model systems.…”

Section: Introductionmentioning

confidence: 99%

siRNA-mediated AML1/MTG8 depletion affects differentiation and proliferation-associated gene expression in t(8;21)-positive cell lines and primary AML blasts

Dunne

Claire

Ritter³

et al. 2006

Oncogene

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The chromosomal translocation t(8;21) is associated with 10-15% of all cases of acute myeloid leukaemia (AML). The resultant fusion protein AML1/MTG8 interferes with haematopoietic gene expression and is an important regulator of leukaemogenesis. We studied the effects of small interfering RNA (siRNA)-mediated AML1/MTG8 depletion on global gene expression in t(8;21)-positive leukaemic cell lines and in primary AML blasts using cDNA arrays, oligonucleotide arrays and real-time reverse transcription-polymerase chain reaction (RT-PCR). Suppression of AML1/MTG8 results in the increased expression of genes associated with myeloid differentiation, such as AZU1, BPI, CTSG, LYZ and RNASE2 as well as of antiproliferative genes such as IGFBP7, MS4A3 and SLA both in blasts and in cell lines. Furthermore, expression levels of several genes affiliated with drug resistance or indicative of poor prognosis AML (BAALC, CD34, PRG2, TSPAN7) are affected by AML1/MTG8 depletion. In conclusion, siRNA-mediated suppression of AML1/MTG8 cause very similar changes in gene expression pattern in t(8;21)-positive cell lines and in primary AML blasts. Furthermore, the results suggest that the specific targeting of AML1/MTG8 function may be a promising approach for complementing existing treatment strategies.

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The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells

Cited by 192 publications

References 29 publications

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

siRNA-mediated AML1/MTG8 depletion affects differentiation and proliferation-associated gene expression in t(8;21)-positive cell lines and primary AML blasts

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