Blood and BM Path Chapter 4 - Regulation of Hematopoiesis

Question 1

CD7

Answer 1

NK and T lymphoid-antigen

Separates NK and T from B lymphocytes

Question 2

Stem cell toxin safeguards

Answer 2

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.

Question 3

HOX gene clusters

Answer 3

• 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”

Question 4

HOX genes in hematopoiesis

Answer 4

• HSCs express HOXB3, HOXB4, HOXA4
  
  • These genes exhibit redundancy for the purpose of hematopoiesis (loss of one will not destroy hematopoietic potential)
• HPCs (asymmetric progeny of HSCs, a form of transit amplifying cell) express HOXA9
  
  • As it happens, most leukemias expressing HOXA9 have a poorer prognosis

Question 5

NUP98-HOX fusions

Answer 5

Fusion of NUP98 with HOX Abd-D genes have been identified as drivers in myeloid leukemias

Question 6

Polycomb genes

Answer 6

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)

Question 7

MEL18

Answer 7

An inhibitory Polycomb gene that inhibits self-renewal rather than promoting it.

Expressed in a reciprocal manner to BMI1.

Question 8

CIP/KIP family members and INK/ARF family members

Answer 8

• CIP/KIP:
  
  • p21
  • p27
  • p57
• INK/ARF:
  
  • p14
  • p15
  • p16
  • p18
  • p19

Question 9

“Stem cell priming”

Answer 9

Expression of most cytokine receptors on stem cells, enabling them to respond to a wide variety of signals.

Question 10

Receptor tyroskine kinases on HSCs

Answer 10

• c-Kit (SCF receptor)
• FLT-3 (FLT-3L receptor)

Question 11

“Cytokine receptor” family

Answer 11

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

Question 12

“gp130” receptor family

Answer 12

Includes receptors for IL-6, IL-11, oncostatin-M, and Leukemia inhibitory factor (LIF)

Question 13

Groups of Wnt receptors

Answer 13

• Frizzled receptors
• Retanoid orphan receptor-2
• LRP5 and 6 (co-receptors)

Question 14

Wnt protien groups

Answer 14

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

Question 15

Dickkopf1

Answer 15

An inhibitor of canonical Wnt signaling (β-catenin mediated)

Question 16

Wnt signaling pathway

Answer 16

Inactive state: APC works together with GSK3β to phosphorylate and ubiquitinate β-catenin, leading to proteasomal degradation.

Question 17

Paradoxical effects of APC loss

Answer 17

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.

Question 18

TGFβ signaling and hematopoiesis

Answer 18

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.

Question 19

Notch family ligands

Answer 19

Jagged-1 and -2

Delta-1, -3, and -4

Question 20

Notch signaling pathway

Answer 20

Proteolysis by gamma secretase releases the Notch intracellular domain (Nicd) which acts as a TF in the nucleus.

Question 21

Basically every Notch ligand results in. . .

Answer 21

. . . proliferation of hematopoietic cells

Question 22

Angiopoietin-like signaling

Answer 22

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.