Hematopoietic Stem Cells Flashcards

Question

Why does removing erythroid-specific enhancer region of BCL11A increase fetal haemoglobin?

Answer 1

Because BCL11A is a repressor of fetal haemoglobin

Answer 2

Extract HSCs form patient bone marrow Gene edit HSC Condition patients bone marrow to receive new stem cells Transplant gene-edited HScs back into patient

Answer 3

Goal is to make space in the bone marrow NICHE for new edited HSCs Myeloablative conditioning = wipe out most of the old HSCs Reduced-intensity conditioning = suppress marrow and immune system without fully destroying it.

Answer 4

It is less step-by-step like in "classical hierarchy" Follows the Continusous Differentiation Model

Answer 5

This model describes the process of HSC differentiation as a gradual, fluid transition where cells progressively acquire lineage-specific characteristics without passing through distinct, clearly defined progenitor stages, instead moving along a continuous spectrum of states towards becoming mature blood cells of different lineages Essentially, it suggests that lineage commitment happens in a smooth, ongoing manner rather than through sharp, discrete steps

Answer 6

HSCs Multipotent Myeloid Progenitors = no self-renewal 1. Common myeloid progenitors = Gives rise to red cells & platelets [Megakaryocyte-Erythroid Progenitor (MEP)] and most innate immune cells [Granulocyte-Macrophage Progenitor (GMP)] 2. Common lymphoid progenitors = Gives rise to adaptive immune cells

Answer 7

They differ in their lineage bias, proliferative behavior, self-renewal potential, and response to stress or aging 1. Single-cell transplantation experiments = if you transplant single HSCs into irradiated mice, the resulting blood production is not uniform 2. Lineage-tracing studies in vivo = showed that different HSCs contribute unequally to blood production over time. 3. Surface marker-defined subpopulations 4. Transcriptional and epigenetic profiling = scRNA-seq show different gene expression programs

Answer 8

In this context, a clone refers to all the descendant cells derived from a single hematopoietic stem cell (HSC), sharing a common origin and unique genetic or molecular marker Clonal tracing uses unique labels (barcodes, mutations, colors) to follow single HSCs and their descendants over time. It reveals the hidden dynamics of blood production—like which cells are active, which are biased, and how the system changes in health and disease.

Answer 9

Spontaneous mutations in mtDNA can serve as natural cellular barcodes in humans

Answer 10

HSCs are largely quiescent but become activated upon stress and ageing

Answer 11

The continuous, balanced production of all blood cell types under normal, non-stressful physiological conditions, ensuring the maintenance of blood and immune system homeostasis. In this state: - Hematopoietic stem cells (HSCs) rarely divide. - Most blood cells are generated by committed progenitors. - The system maintains a stable output of red cells, white cells, and platelets to replace those naturally lost. It contrasts with emergency or stress hematopoiesis, where HSCs are actively recruited to divide and respond to injury, infection, or blood loss.

Answer 12

Chronic increase in inflammation due to age and stress = causes reduction of HSC diversity and clonal expansion

Answer 13

Accumulation of 2-19 oncogenic mutations HSC scquire ~ 17 somatic mutation per year Only about 2-3 are coding mutations per 10 years

Answer 14

An "oncogenic mutation" is a specific type of genetic change that directly contributes to cancer development by activating a gene that promotes cell growth (proto-oncogene, becoming an oncogene) While a "somatic mutation" is a broader term referring to any genetic change that occurs in a body cell (not in sperm or egg) during an organism's lifetime

Answer 15

A type of acute leukemia that occurs when the MLL gene on chromosome 11q23 is rearranged. This can lead to aggressive leukemias that affect both children and adults.

Answer 16

When the MLL gene on chromosome 11q23 is rearranged

Answer 17

Promotes DNMT3A-mutated clonal hematopoiesis

Answer 18

DNA methyltransferase 3 alpha, is an enzyme primarily responsible for establishing new DNA methylation patterns during early development = when mutated drives clonal hematopoiesis DNMT3A mutation induces accumulation of quiescent LT-HSCs = these are less senstiive ti differentiation cues and chemotherapy (after infection)

Answer 19

Mutations affecting DNA methylation (DNMT3A) in healthy individuals increase risk of devloping AML And occur years before diagnosis

Answer 20

Clonal expansion of premalignant stem cells As well as emergene of leukemic stem cells from HSCs or differentiated progeny

Answer 21

Ten-eleven translocation 2 (TET2) is a protein that regulates DNA demethylation It is important for the function of hematopoietic stem cells (HSCs). TET2 mutations are common in hematological malignancies and clonal hematopoiesis

Answer 22

Therapy-resistance Plasticity = response to stressors Clonal evolution

Answer 23

Upon stressors = ageing, inflammation, and blood loss

Answer 24

Have capacity to enter reversible state of quiescnece/domrnacy Thorught to resist standard chemotherpay and form cellular reservoir that drives relapse by re-initiating the disease after remissoin Also they sit at top of hierarchy of more differentiated cells

Answer 25

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the expansion of hematopoietic cells harboring leukemia-associated somatic mutations in otherwise healthy people and occurs in at least 10% of adults over 70 Acquisition of pre-leukemic mutation in singla HSC (DNMT3A or TET2) Results in proliferative advantage and clonal outgorwth of one HSC clone All progeny inherit the same mutation

Answer 26

NPM1= Nucleophosmin 1 A protein primarily located in the nucleolus of a cell and plays a crucial role in various cellular functions including ribosome biogenesis, DNA repair, histone chaperoning, and regulation of the cell cycle, with its most significant function being the maintenance of genomic stability by shuttling between the nucleus and cytoplasm

Answer 27

Mutation causes the protein to mislocalize to the cytoplasm instead of staying in the nucleolus. This can impair ribosome biogenesis, leading to altered cellular function. Altered cell cyle regulation leading to uncontrolled cell division. This contributes to the uncontrolled proliferation of leukemia cells. Impair the protein's role in DNA repair mechanisms, increasing the risk of genetic instability in the cell, which promotes the development of Increased Oncogenic Signaling: The mutated form of NPM1 can affect the activity of other signaling molecules and pathways, including those that regulate cell survival, differentiation, and apoptosis. This can promote the survival and expansion of leukemic cells. NPM1 mutations are often found in conjunction with other mutations, such as those in the FLT3 receptor (which is involved in cell signaling and growth). This combined genetic impact contributes to the development and progression of leukemia.