Blood and BM Path Chapter 4 - Regulation of Hematopoiesis Flashcards
CD7
NK and T lymphoid-antigen
Separates NK and T from B lymphocytes
Stem cell toxin safeguards
Stem cells express p-glycoprotein (aka MDR1) and breast cancer related protein (BCRP), which extrude toxins from the cell.
This helps protect the “stem” genome.
HOX gene clusters
- There are four HOX clusters in humans (A-D) located on different chromosomes
- Generally speaking, in terms of body plan, 3’ HOX genes are expressed towards the head, 5’ HOX genes are expressed towards the “tail”
HOX genes in hematopoiesis
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HSCs express HOXB3, HOXB4, HOXA4
- These genes exhibit redundancy for the purpose of hematopoiesis (loss of one will not destroy hematopoietic potential)
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HPCs (asymmetric progeny of HSCs, a form of transit amplifying cell) express HOXA9
- As it happens, most leukemias expressing HOXA9 have a poorer prognosis
NUP98-HOX fusions
Fusion of NUP98 with HOX Abd-D genes have been identified as drivers in myeloid leukemias
Polycomb genes
Regulators of chromatin-condensation proteins and initiation transcription machinery that help control cell proliferation, senescence, and death.
They are regulators of the HOX genes and modify the expression of p16INK4a and p19ARF.
Organize into “Polycomb regulatory complexes”, or PRCs:
- PRC1: EZH, EED, SUZ12
- PRC2: BMI1, RAE28 (drives self-renewal, antagonize INK/ARF family expression)
MEL18
An inhibitory Polycomb gene that inhibits self-renewal rather than promoting it.
Expressed in a reciprocal manner to BMI1.
CIP/KIP family members and INK/ARF family members
- CIP/KIP:
- p21
- p27
- p57
- INK/ARF:
- p14
- p15
- p16
- p18
- p19
“Stem cell priming”
Expression of most cytokine receptors on stem cells, enabling them to respond to a wide variety of signals.
Receptor tyroskine kinases on HSCs
- c-Kit (SCF receptor)
- FLT-3 (FLT-3L receptor)
“Cytokine receptor” family
As opposed to RTKs, cytokine receptors lack intrinsic tyrosine kinase capabilities.
Rather, they associate with cellular kinases, such as JAK (to activate STAT signaling) or Ras
“gp130” receptor family
Includes receptors for IL-6, IL-11, oncostatin-M, and Leukemia inhibitory factor (LIF)
Groups of Wnt receptors
- Frizzled receptors
- Retanoid orphan receptor-2
- LRP5 and 6 (co-receptors)
Wnt protien groups
Generally grouped according to downstream signaling cascades:
- “Canonical” / β-catenin-mediated
- β-catenin recrutis Tcf/Lef and translocates to nucleus
- Tcf/Lef acts on HOX genes and cell cycle regulators
- “Non-canonical” / β-catenin independent
Dickkopf1
An inhibitor of canonical Wnt signaling (β-catenin mediated)
Wnt signaling pathway
Inactive state: APC works together with GSK3β to phosphorylate and ubiquitinate β-catenin, leading to proteasomal degradation.
Paradoxical effects of APC loss
Generally APC loss causes dysregulated Wnt signaling, which in the gut results in familial adenomatous polyposis, actually causes severe HSC depletion and anemia!
It is thought these effects on hematopoiesis may be mediated by a pathway independent of canonical Wnt signaling.
Though poorly studied, there is a suspicion that APC deletions also play a role in MDS and myeloid neoplasms.
TGFβ signaling and hematopoiesis
Poorly studied, but thought to play some role – especially the BMP4 family, which helps regulate development of the mesoderm.
Of note, a lot of TGF knockouts are embryonic lethal phenotypes.
SMAD7 overexpression results in increased self-renewal.
Notch family ligands
Jagged-1 and -2
Delta-1, -3, and -4
Notch signaling pathway
Proteolysis by gamma secretase releases the Notch intracellular domain (Nicd) which acts as a TF in the nucleus.
Basically every Notch ligand results in. . .
. . . proliferation of hematopoietic cells
Angiopoietin-like signaling
Interaction between Tie2 (tyrosine kinase on HSCs) and angiopoietin-1 (expressed by osteoblasts lining the BM cavity) promotes HSC quiescence.
This prevents the HSC pool from “crowding” the marrow too much.
