miR-328 Functions as an RNA Decoy to Modulate hnRNP E2 Regulation of mRNA Translation in Leukemic Blasts

Granulocytes and monocytes develop from a common myeloid progenitor. Early granulopoiesis requires the C/EBPalpha, PU.1, RAR, CBF, and c-Myb transcription factors, and terminal neutrophil differentiation is dependent upon C/EBPepsilon, PU.1, Sp1, CDP, and HoxA10. Monopoiesis can be induced by Maf-B, c-Jun, or Egr-1 and is dependent upon PU.1, Sp1, and ICSBP. Signals eminating from cytokine receptors modulate factor activities but do not determine cell fates. Orchestration of the myeloid developmental program is achieved via cooperative gene regulation, via synergistic and inhibitory protein-protein interactions, via promoter auto-regulation and cross-regulation, via regulation of factor levels, and via induction of cell cycle arrest: For example, c-Myb and C/EBPalpha cooperate to activate the mim-1 and NE promoters, PU.1, C/EBPalpha, and CBF, regulate the NE, MPO, and M-CSF Receptor genes. PU.1:GATA-1 interaction and C/EBP suppression of FOG transcription inhibits erythroid and megakaryocyte gene expression. c-Jun:PU.1, ICSBP:PU.1, and perhaps Maf:Jun complexes induce monocytic genes. PU.1 and C/EBPalpha activate their own promoters, C/EBPalpha rapidly induces PU.1 and C/EBPepsilon RNA expression, and RARalpha activates the C/EBPepsilon promoter. Higher levels of PU.1 are required for monopoiesis than for B-lymphopoiesis, and higher C/EBP levels may favor granulopoiesis over monopoiesis. CBF and c-Myb stimulate proliferation whereas C/EBPalpha induces a G1/S arrest; cell cycle arrest is required for terminal myelopoiesis, perhaps due to expression of p53 or hypo-phosphorylated Rb.

Transcriptional regulation of granulocyte and monocyte development

STAT3 controls myeloid progenitor growth during emergency granulopoiesis

Transcriptional regulation in myelopoiesis: Hematopoietic fate choice, myeloid differentiation, and leukemogenesis

The human CD34(+)/CD38(-)/Lin(-) cell subset, comprising approximately 1-10% of the CD34(+) cell population, contains few of the less primitive hematopoietic (lineage-committed) progenitor cells (HPCs) but most of the primitive in vivo engrafting (lympho-)hematopoietic stem cells (HSCs). We analyzed gene expression in CD34(+)/CD38(-)/Lin(-) cell populations isolated from normal human adult donor bone marrow, neonatal placental/umbilical cord blood, and mobilized adult donor peripheral blood stem-progenitor cells. As measured by Affymetrix microarrays, 4746 genes were expressed in CD34(+)/CD38(-)/Lin(-) cells from all three tissues. We also determined the transcriptomes of the stem cell-depleted, HPC-enriched CD34(+)/[CD38/Lin](++) cell population from each tissue. Comparison of CD34(+)/CD38(-)/Lin(-) (HSC-enriched) versus CD34(+)/[CD38/Lin](++) (HPC-enriched, HSC-depleted) cells from each tissue yielded 81 genes overrepresented and 90 genes underrepresented, common to all three of the CD34(+)/CD38(-)/Lin(-) cell populations. These transcripts, which are selectively expressed in HSCs from all three tissues, include a number of known genes (e.g., transcription factors, receptors, and signaling molecules) that might play roles in key functions (e.g., survival, self-renewal, differentiation, and/or migration/adhesion) of human HSCs. Many genes/transcripts of unknown function were also detected by microarray analysis. Serial analysis of gene expression of the bone marrow HSC and HPC populations confirmed expression of most of the overrepresented transcripts for which reliable serial analysis of gene expression tags were detected and additionally suggested that current microarrays do not detect as many as 30% of the transcripts expressed in HSCs, including a number of previously unknown transcripts. This work is a step toward full definition of the transcriptome of normal human HSCs and may identify new genes involved in leukemogenesis and cancer stem cells.

https://cancerres.aacrjournals.org/content/canres/64/13/4434.full.pdf

Microarray and serial analysis of gene expression analyses identify known and novel transcripts overexpressed in hematopoietic stem cells.

Chromosomal rearrangements involving the two subunits of the heterodimeric transcription factor, core-binding factor (CBF), are the most commonly observed cytogenetic abnormalities in adult acute myeloid leukemia (AML). CBF is comprised of one of three potential DNA-binding α subunits (RUNX1, RUNX2, or RUNX3)1 that interact with a nonDNA-binding subunit, CBFβ. The major rearrangement affecting CBFβ generates the inv(16)(p13.1q22), which fuses the first 165 amino acids of CBFβ with the coiled-coil rod domain of the smooth muscle myosin heavy chain (SMMHC) gene, MYH11.2,3 The resulting CBFβ-SMMHC fusion protein retains the ability to interact with RUNX1, and functions by dominantly inhibiting normal CBF activity. This view is supported by studies where CBFβ-MYH11 was knocked into the endogenous CBFβ locus, which resulted in an

The assembly competence domain is essential for inv(16)-associated acute myeloid leukemia

To assess cooperation between G-CSF signals and C/EBPα, we characterized Ba/F3 pro-B cell lines expressing C/EBPαWT-ER and the G-CSF receptor (GCSFR). In these lines, GCSFR signals can be evaluated independent of their effect on C/EBPα levels. G-CSF alone did not induce the MPO, NE, LF, or PU.1 RNAs, and C/EBPαWT-ER alone stimulated low-level MPO and high-level PU.1 expression. Simultaneous activation of the GCSFR and C/EBPαWT-ER markedly increased MPO and NE induction at 24 h, and LF mRNA was detected at 48 h. G-CSF did not increase endogenous GCSFR, endogenous C/EBPα or exogenous C/EBPαWT-ER levels, and C/EBPαWT-ER did not induce endogenous or exogenous GCSFR. Several GCSFR mutants were also co-expressed with C/EBPαWT-ER. Mutation of all four cytoplasmic tyrosines prevented NE induction but enhanced MPO induction. Mutation of Y704 was required for increased MPO induction. Consistent with this finding, removing IL-3 without G-CSF addition enabled MPO, but not NE, induction by C/EBPαWT-ER. GCSFR signals or related signals from other receptors may cooperate with C/EBPα to direct differentiation of normal myeloid stem cells.

C/EBPα and G-CSF receptor signals cooperate to induce the myeloperoxidase and neutrophil elastase genes

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The assembly competence domain is essential for inv(16)-associated acute myeloid leukemia

C/EBPα and G-CSF receptor signals cooperate to induce the myeloperoxidase and neutrophil elastase genes