Ch7.10 NF1

Question 1

What is the primary target of LOH in neurofibromas?

Answer 1

Schwann cell precursors are the primary targets of loss of heterozygosity (LOH) in neurofibromas.

Question 2

What happens once Schwann cell precursors lose all NF1 function?

Answer 2

They orchestrate the development of neurofibromas by inducing co-proliferation of other cell types via paracrine signaling.

Question 3

What is the significance of paracrine signaling in neurofibroma formation?

Answer 3

It causes various neighboring cell types to proliferate in response to signals from neoplastic Schwann cells.

Question 4

How does an NF1+/- genotype affect neighboring cells in neurofibromas?

Answer 4

Neighboring cells with an NF1+/- genotype may be hyper-responsive to paracrine signals due to reduced NF1 protein levels.

Question 5

What role do mast cells play in neurofibroma formation?

Answer 5

Mast cells, recruited via paracrine signals from NF1-/- Schwann cells, are critical to the development of neurofibromas.

Question 6

How does the genotype of bone marrow cells affect neurofibroma formation?

Answer 6

When bone marrow cells are NF1+/+, they are less responsive to paracrine signals, reducing the formation of neurofibromas.

Question 7

What happens to neurofibroma development when mast cells are NF1+/+?

Answer 7

There is a drastic reduction in neurofibroma formation, suggesting NF1 haploinsufficiency in mast cells promotes tumor development.

Question 8

What is haploinsufficiency in the context of NF1?

Answer 8

Haploinsufficiency refers to the insufficient amount of NF1 protein in NF1+/- cells, which leads to abnormal tumor-promoting behavior.

Question 9

What question does the NF1+/- phenotype raise about tumor suppressor genes?

Answer 9

It raises the possibility that half-dosage of tumor suppressor proteins may result in subtle but important changes in cell behavior.

Question 10

What is the broader significance of NF1 haploinsufficiency in tumor suppressor gene research?

Answer 10

It suggests that partial loss of tumor suppressor function could contribute to tumor development even before full loss occurs.

Question 11

What are plexiform neurofibromas?

Answer 11

Tumors occurring at nerve roots that emerge from the spinal cord, common in mice heterozygous at the NF1 locus (NF1+/-).

Question 12

How does the recruitment of mast cells influence neurofibroma development?

Answer 12

Increased recruitment of mast cells enhances neurofibroma formation, especially in the NF1+/- context.

Question 13

What happens if NF1+/+ bone marrow cells are present in NF1+/- mice?

Answer 13

Neurofibroma formation is significantly reduced due to lower recruitment of mast cells to the tumor site.

Question 14

What is neurofibromin, and what is its known function?

Answer 14

Neurofibromin is a large protein encoded by the NF1 gene, with a Ras-GAP domain that negatively regulates Ras signaling.

Question 15

What percentage of neurofibromin is composed of its Ras-GAP domain?

Answer 15

The Ras-GAP domain encompasses only 10% of the neurofibromin protein.

Question 16

Why is neurofibromin unique among Ras-GAPs in causing neurofibromas?

Answer 16

Although there are 14 Ras-GAPs in the human genome, only neurofibromin is associated with neurofibroma formation.

Question 17

What unknown roles might neurofibromin play beyond its Ras-GAP function?

Answer 17

Neurofibromin likely has other, yet-uncharacterized functions that may contribute to its role in tumorigenesis.

Question 18

Why is the diversity of Ras-GAPs in the human genome significant?

Answer 18

The presence of many Ras-GAPs suggests specialized functions, with NF1 being uniquely involved in neurofibroma formation.

Question 19

What is the link between NF1 and juvenile myelomonocytic leukemia (JMML)?

Answer 19

NF1 heterozygotes have a 300-fold increased risk of developing JMML due to neurofibromin’s role in regulating myeloid cell proliferation.

Question 20

How does NF1 function in myeloid cells?

Answer 20

Neurofibromin regulates the proliferation of myeloid cells, with loss of function contributing to the risk of leukemia.

Question 21

What do genetically altered mice reveal about NF1?

Answer 21

Mice heterozygous for NF1 (NF1+/-) develop plexiform neurofibromas, similar to the human condition.

Question 22

How do NF1+/+ bone marrow cells affect NF1+/- mice?

Answer 22

NF1+/+ bone marrow cells reduce the formation of plexiform neurofibromas, indicating the importance of NF1 haploinsufficiency in tumor formation.

Question 23

What is the role of paracrine signaling in NF1-related tumors?

Answer 23

NF1-/- Schwann cells release signals that drive the proliferation of nearby NF1+/- cells, promoting tumor growth.

Question 24

Why are NF1+/- cells more susceptible to paracrine signals?

Answer 24

The reduced NF1 protein levels in NF1+/- cells make them more responsive to growth-stimulatory signals.

Question 25

How do multiple cell types collaborate in tumor formation?

Answer 25

In neurofibromas, NF1-/- Schwann cells and recruited NF1+/- mast cells cooperate to drive tumor development.

Question 26

What does this cellular collaboration suggest about tumor biology?

Answer 26

Tumor formation often involves interactions between mutant and non-mutant cell types, with paracrine signaling playing a key role.

Question 27

What is chromosomal instability (CIN)?

Answer 27

CIN is the tendency for cells to acquire abnormal chromosome numbers, often due to defective segregation during mitosis.

Question 28

How does NF1 loss contribute to chromosomal instability?

Answer 28

Loss of NF1 function has been linked to increased chromosomal instability, facilitating tumor progression.

Question 29

What might CIN explain in terms of tumorigenesis?

Answer 29

CIN may accelerate the accumulation of genetic changes, promoting the development of malignant phenotypes in tumors.

Question 30

What are some unanswered questions about neurofibromin?

Answer 30

Future research may uncover additional roles for neurofibromin beyond Ras regulation, potentially revealing new mechanisms of tumorigenesis.

Question 31

Why might neurofibromin have other significant functions?

Answer 31

The fact that its Ras-GAP domain is only a small part of the protein suggests other domains could be important for cellular regulation.

Question 32

What is the role of tumor suppressor genes (TSGs)?

Answer 32

TSGs prevent uncontrolled cell growth, and their inactivation can lead to cancer.

Question 33

How does NF1 function as a tumor suppressor?

Answer 33

NF1 encodes neurofibromin, which negatively regulates Ras signaling, a key pathway in cell growth control.

Question 34

What happens when both NF1 alleles are lost in Schwann cells?

Answer 34

Complete loss of NF1 function in Schwann cells leads to neurofibroma formation.

Question 35

Why is full NF1 loss necessary for tumor formation?

Answer 35

While NF1+/- cells exhibit abnormal behavior, full NF1 inactivation is required for tumor initiation and progression.

Question 36

What is the function of Ras-GAP proteins?

Answer 36

Ras-GAPs regulate Ras activity, ensuring controlled cell growth and proliferation.

Question 37

How does neurofibromin differ from other Ras-GAPs?

Answer 37

Neurofibromin’s involvement in neurofibromas is unique, suggesting specific roles in certain tissues.

Question 38

What does the NF1 gene encode?

Answer 38

The NF1 gene encodes neurofibromin, a protein that helps regulate cell growth by acting as a Ras-GAP.

Question 39

What might future studies on neurofibromin reveal?

Answer 39

Future research may identify novel functions of neurofibromin, further linking it to different aspects of tumor biology.

Question 40

Why is neurofibromin critical for normal cell behavior?

Answer 40

Neurofibromin’s regulation of Ras signaling is essential for preventing uncontrolled cell proliferation and tumor formation.