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Clinical Pathology > Introduction to Leukaemias > Flashcards

Introduction to Leukaemias Flashcards

1
Q

Define Leukemia

A

Malignant Disorder
Of Haematopoietic Stem Cells
Associated with increase in number of WBCs (of any type)/ WBC precursors
Seen in BM/ peripheral blood

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2
Q

What are the 2 lineages of blood cells and what types of cells do they form?

A

Myeloid lineage gives rise to platelets (thrombopoiesis), RBCs (erythropoiesis) and WBCs (granulocytes, monocytes which form macrophages)

Lymphoid lineage gives rise to B and T cells and NK cells

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3
Q

What are 2 important characteristics of haematopoietic stem cells? Which of these are shared by progenitor cells too?

A
  1. Pluripotent - can give rise to any cell of any lineage

2. Self maintaining - can divide to produce more stem cells to prevent depletion. Progenitors can do this too.

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4
Q

What is the life cycle of a progenitor?

A

Divisions (definitive amount)

Differentiate and mature

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5
Q

How are progenitors multipotent and then unipotent?

A

They are multipotent as they can develop into any cell type of any lineage

But they then commit to forming, when mature, one type of cell only (i.e. commit to 1 lineage so are unipotent)

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6
Q

What is a morphological characteristic of progenitor cells?

A

You cannot tell the difference between them morphologically as they do not show characteristics of mature cells, even when unipotent (committed to 1 lineage)

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7
Q

Describe the process by which leukaemia occurs and thus how it is a clonal disease?

A

1 haematopoietic stem cell gets a mutation

This drives oncogenic TFs to arrest the cell (so no differentiation/ maturation of progenitor cell) - cell is in preleukaemic state now

2nd hit (UV ray to trigger oncogenic mechanism) causes high proliferation, low differentiation and no apoptosis - cell cannot die so build up of lots of pre-mature cells occurs i.e. full blown leukaemia

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8
Q

Describe the incidence rate of leukaemia

A

There is a higher rate in older people + men compared to women

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9
Q

How does someone with leukaemia typically first present?

A

There is a loss of normal blood cell production

Platelet loss - abnormal bruising
WBC loss - repeating infection
RBC loss - anaemia

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10
Q

Why is leukaemia said to be a polyetiological disease?

A

A combination of factors are involved in causing it - genetic, environmental and lifestyle

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11
Q

What type of mutations often cause leukaemia, somatic or hereditary?

A

Somatic - except CLL

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12
Q

What genetic diseases predispose someone to getting leukaemia?

A

Fanconi’s Anaemia and Down Syndrome

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13
Q

What are the potential genetic problems that can contribute to leukaemia?

A
  1. Activating mtns (oncogenes)
  2. Deactivating mtns (TSGs)
  3. Mtn in genes of other diseases (TP53 in Li-Fraumeni, NF1 in neurofibromatosis, RAS pathway)
  4. Chromosomal changes e.g. translocations (BCR-ABL in CML and PML-RAR in AML)/ numerical disorders (Downs - ALL)

Usual genetic alterations are chromosome translocations. They involve genes for TFs that control cell differentiation.

  1. Inherited immune system problem (e.g. in ataxia-telangiectasia/ Wiskott-Aldrich)
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14
Q

What are the potential environmental problems that can contribute to leukaemia?

A
  1. Exposure to radiation (acute radiation accident/ atomic bomb)
  2. Exposure to chemicals/ chemotherapy (alkylating agents like Busulphan - AML/ industrial exposure to benzene)
  3. Immune system suppression (e.g. after organ transplant you have suppression so an increased risk of developing leukaemia)
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15
Q

What are the potential lifestyle related risk factors for leukaemia?

A

Smoking, drinking, excessive exposure to sun, being overweight

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16
Q

What are the risk factors for leukaemia that require more studies to validate/ are controversial?

A
  1. Exposure to electromagnetic fields in pregnancy
  2. Nuclear Power Stations
  3. Infections early in life
  4. Mothers age when child is born
  5. Parents smoking history
  6. Foetal exposure to hormones
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17
Q

What are the 4 types of leukaemia?

A
  1. Acute Lymphoid (or acute lymphoblastic)
  2. Acute Myeloid (or acute myeloblastic)
  3. Chronic Lymphoid (or chronic lymphocytic)
  4. Chronic Myeloid (or chronic myelocytic)
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18
Q

What are the characteristics of acute diseases?

A

Rapid onsets
Severe course
Short course

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19
Q

What kind of cells accumulate in BM/ blood in acute leukaemias? How do they accumulate?

A

Undifferentiated and immature cells, also known as -blast cells

Uncontrolled clonal division (only a single stem cell was mutated to cause it) of immature WBCs (myeloblasts and lymphoblasts)

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20
Q

What is a chronic disease?

A

Persists over a long time

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21
Q

What kind of cells accumulate in BM/ blood in chronic leukaemias? How do they accumulate?

A

Differentiated and mature cells, also known as -cyte cells

Uncontrolled clonal division (single stem cell effected only) of mature WBCs

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22
Q

What is the age, way of onset, duration and WBC count for acute and chronic leukaemias?

A

Age - children for acute, middle age and elderly for chronic

Onset - sudden for acute and slow for chronic

Duration - weeks to months for acute and years for chronic

WBC count - variable for acute and high for chronic

23
Q

Which cancer is the most common of cancers in children?

A

Acute leukaemia - 75% of those are acute lymphoblastic and 25% are acute myeloblastic

24
Q

Why can you find a lot of blast cells in peripheral blood for those with acute leukaemia?

A

There is a stop to the formation of mature cells, causing blast cells to accumulate (as lots of proliferation but do not mature or die)

25
Q

What are the symptoms for acute leukaemia? What prevents the symptoms from appearing?

A

All due to BM suppression and inappropriate production of blood cells

Platelets - bruising (purpura), epitaxis (nosebleed), bleeding from gums

WBCs - Neutropenia (low neutrophils) - recurrent infections and fever

RBCs - anaemia - weakness, tiredness, shortness of breath, lassitude (physical/ mental lack of energy)

Antibiotics

26
Q

How do you diagnose acute leukaemia?

A
  1. Blood test - peripheral blood blast test or PB checks for prescence of blast cells or cytopenia (lack of cells). If value of blasts >30% then suspected to have acute leukaemia.
  2. BM biopsy - take from pelvic bone’s BM to see if there is a high concentration of blast cells there
  3. Lumbar puncture - to see if the leukaemia has spread to the CSF
27
Q

How can you analyze cells to see if there is acute leukaemia present?

A
  1. Cytomorphology study - stain cells and see under microscope
  2. Immuno-phenotyping - use antibodies to bind markers on cells
  3. Flow Cytometry - finds types of cells in the sample
  4. NGS/ FISH - sees genetic profile of cells (sees if there are any genetic causes which would tell type of leukaemia, inform of prognosis and influence treatment given based on usual response)
28
Q

How can acute lymphoblastic leukaemia be classifed?

A

B-cell or T-cell leukaemia

29
Q

What is the treatment and outcomes for acute lymphoblastic leukaemia?

A

Treatment - chemotherapy (oral, IV, IM, intrathecal)

1 in 10 ALL patients relapse. 50% of those who have 2nd chemotherapy/ BM transplant go into remission.

30
Q

Why do adults with acute lymphoblastic leukaemia have poorer prognosis?

A

Disease has different cell of origin/ oncogene mtns than when the disease presents in children

31
Q

How is acute myeloblastic leukaemia classified?

A

A FAB system uses grades M0-M7 based on:

  1. Stage of differentiation arrest occured on e.g. promyelocytic anaemia
  2. Main cell type e.g. erythroleukaemia
32
Q

How can you differentiate between acute lymphoblastic and myeloblastic leukaemia? Why is this process needed?

A

Take BM biopsy and do cytomorphological study to see predominant blast cells. Can also use cell surface markers.

Needed as they both share the same symptoms (more bleeding in ALL patients)

33
Q

What are the treatments and outcomes for acute myeloblastic leukaemia?

A
  1. Chemotherapy (oral, IV, IM, IT)
  2. Monocolonal antibodies for cell surface markers
  3. Allogeneic bone marrow transplant (stem cells used from donor)

5 year survival rate is lower than acute lymphoblastic leukaemia

34
Q

What is the commonest type of leukaemia overall?

A

Chronic Lymphocytic Leukaemia

35
Q

What are the symptoms for chronic lymphocytic leukaemia?

A

Typical symptoms (bruising, recurrent infections, anaemia) as well as lymph node, liver and spleen enlargement (hepatosplenomegaly)

36
Q

What are the treatments and outcome for chronic lymphocytic leukaemia?

A

Chemotherapy to reduce cell numbers

Many patients survive for more than 12 years - decent outcome

37
Q

What are the symptoms for chronic myelocytic leukaemia?

A

Usually asymptomatic, but can show typical symptoms (anaemia, bruising, recurrent infections) + splenomegaly (LUQ fullness/ pain) + weight loss

Often found in regular blood tests

38
Q

How is chronic myelocytic leukaemia diagnosed?

A

High WBC in blood and BM

These cells have chromosome changes e.g. philadelphia chromosome

39
Q

What are the treatments and outcome for chronic myelocytic leukaemia?

A

Chemotherapy
Imatinib
Allogeneic BM transplant - best just to do this to prevent accelerated phase and blast crisis (when more than 30% of the cells in the blood or bone marrow are blast cells)

High 5 year survival is high

40
Q

What is a philadelphia chromosome?

A

Translocation between long arms of chromosome 9 and 22

Forms a changed chromosome 9 and changed chromosome 22. The chromosome 22 is the Philadelphia chromosome. It has a BCR gene which was originally there and an ABL gene from chromosome 9.

The PC is found in 95% of cases of CML

41
Q

The BCR-ABL translocation can give rise to isoforms/ variants. Which variants are characteristic of chronic myeloid leukaemia and acute lymphoid leukaemia?

A

210 BCR-ABL is characteristic of chronic myeloid leukaemia and 185 BCR-ABL is characteristic of the acute lymphoid leukaemia

42
Q

What do the BCR and ABL genes separately encode and why is it oncogenic if they fuse together?

A

BCR - protein acting as a guanine nucleotide exchange factor for Rho GTPase proteins

ABL - tyrosine kinase with tight regulation (auto-inhibition + via it’s promoter)

When the translocation occurs, the ABL genes promoter is lost. This rids of the self control for the protein. The ABL protein gets controlled by the BCR genes first part, which up regulates the tyrosine kinase activity

43
Q

What does the upregulation of tyrosine kinase activity cause? (referring to the Philadelphia chromosome)

A
  1. Proliferation of progenitor cells in the absence of GFs
  2. Decreased apoptosis
  3. Decreased adhesion of cells to BM stroma

This all causes CML

44
Q

How do you diagnose for chronic myeloid leukaemia?

A

Detect the Philadelphia chromosome i.e. by using fluorescent probes to detect the BCR-ABL fusion

45
Q

How is the information about the BCR-ABL oncogene useful?

A
  1. You can use it to diagnose chronic myeloid leukaemia
  2. You can use it to see if there is any minimal residual disease after treatment
  3. You can target it with drugs e.g. Imatinib inhibits BCR-ABL
46
Q

What are the therapies available for leukaemias?

A
  1. Chemotherapy
  2. Targeted Therapy
  3. Stem Cells and Bone Marrow transplants
47
Q

Compare and contrast targeted therapies with chemotherapy

A

Targeted therapies are oral agents that interact with specific molecular targets (proteins involved in certain pathways/ mechanisms) associated with cancer, so only effect them and not surrounding tissues

Chemo therapies are intravenous (some oral) agents that act on all rapidly dividing cells so are not specific

48
Q

What kind of cells can chemotherapeutic drugs act on? What do they do?

A

Skin cells, hair follicles, BM cells, GI epithelium

Break DNA double strands and substitute in nucleotides

49
Q

What are 2 examples of chemotherapeutic drugs and how they work?

A 
Cytosine arabinoside
Cytosine analogue
Interferes with deoxynucleotide synthesis
Prevents DNA replication
Treats AML

Vincristine
Binds tubullin dimers
So inhibits microtubule formation in mitotic spindle
Treats ALL

50
Q

What is used for targeted therapy?

A

Tyrosine Kinase inhibitors (e.g. Imatinib)
Inhibits BCR-ABL tyrosine kinase
To cause apoptosis of CML cells
So treats CML

51
Q

What are stem cell and bone marrow transplants mainly used to treat? What do they allow to occur?

A

AML - high remission rates with aggressive treatment so successful but elderly unable to tolerate aggressive treatment

Haematopoiesis to start again (reconstitute) from an inactive (quiescent) stem cell pool

52
Q

What is the difference between an allogeneic and autologous transplant?

A

Allogeneic transplants use stem cells from donors but autologous use stem cells obtained from the same person

53
Q

Describe the process of allogeneic and autologous transplants

A

Allogenic transplant

Stem cells from donor are treated (purified/ concentrated/ cryo-preserved)
Patient receives high doses of chemotherapy and radiation therapy.
When immunosuppressed, the donor stem cells are defrosted and transfected into the patient
Therefore regenerate pool of stem cells via another person

Autologous transplant

Collect stem cells
Purify
Patient receives high doses of chemotherapy and radiation therapy
When all the leukaemia cells have been removed from the patient, the healthy stem cells are transfused in
So the patient can give rise to healthy cells again due to themselves

54
Q

What are the 3 major types of blood cancers?

A

Leukaemia, Lymphoma, Myeloma

Clinical Pathology (5 decks)

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