Essential role of Jun family transcription factors in PU.1 knockdown–induced leukemic stem cells

Abstract

Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. Restoration of c-Jun expression in preleukemic cells rescued the PU.1 knockdown-initiated myelomonocytic differentiation block. Lentiviral restoration of JunB at the leukemic stage led to loss of leukemic self-renewal capacity and prevented leukemia in NOD-SCID mice into which leukemic PU.1-knockdown cells were transplanted. Examination of human individuals with AML confirmed the correlation between PU.1 and JunB downregulation. These results delineate a transcriptional pattern that precedes leukemic transformation in PU.1-knockdown HSCs and demonstrate that decreased levels of c-Jun and JunB contribute to the development of PU.1 knockdown-induced AML by blocking differentiation and increasing self-renewal. Therefore, examination of disturbed gene expression in HSCs can identify genes whose dysregulation is essential for leukemic stem cell function and that are targets for therapeutic interventions.

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…1,2,8,9,20,41 It has been shown that leukemia-initiating cells can reside in different phenotypic stem and progenitor compartments at relatively low frequencies and are associated with transcription factor alterations that result in pathogenic transcriptional changes. [2][3][4][5][6][7][11][12][13]32,[42][43][44] Thus, to uncover newer stem cell-directed targets, we conducted a transcriptomic analysis on rigorously defined stem and progenitor populations in AML and MDS in comparison with their respective healthy counterparts. With this approach, we were able to identify IL8 as one of the few genes most significantly overexpressed across different stem and progenitor subsets in AML and MDS patients, indicating it might play a crucial role in the pathogenesis of AML and MDS.…”

Transcriptional control of granulocyte and monocyte development

“…The C/EBPa LZ also competes with c-Jun for interaction with PU.1 in the absence of DNA (Reddy et al, 2002), but when bound to DNA C/EBPa may in specific contexts, like C/EBPb, augment PU.1 activity as these factors cooperatively activate myeloid promoters (Oelgeschla¨ger et al, 1996). c-Jun rescues monocytic differentiation in PU.1-knockdown marrow cells (Steidl et al, 2006), but its effect in PU.1(À/À) cells has not been evaluated. Also of note, c-Jun and JunB levels are reduced in PU.1-knockdown HSCs, although PU.1 binds the JunB but not the c-Jun promoter (Steidl et al, 2006).…”

“…c-Jun rescues monocytic differentiation in PU.1-knockdown marrow cells (Steidl et al, 2006), but its effect in PU.1(À/À) cells has not been evaluated. Also of note, c-Jun and JunB levels are reduced in PU.1-knockdown HSCs, although PU.1 binds the JunB but not the c-Jun promoter (Steidl et al, 2006). c-Jun or c-Fos interacts with and prevents C/EBP bZIP DNA-binding, even if the c-Fos or c-Jun BRs are deleted, suggesting direct interaction via their LZ domains (Hsu et al, 1994).…”

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…In contrast, other transcription factors, (for example, PU.1 and JunB) may display reduced expression in AML stem cells. 178,179 Targeting of transcription factors has proven problematic, however, it is an area which has great potential. 180 In summary specific therapeutic targeting of the leukemic stem cells is a field in its infancy.…”