UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.

1. Abdul-Kader Souid
↓ Neutrophil Count (Neutropenia)
• Inherited (bone marrow examination is necessary):
• Neutropenia, severe congenital, 1, AD; SCN1 (MIM#202700); mutations in
ELANE (MIM#130130)
• Cyclic neutropenia, AD (MIM#162800); mutations in ELANE
(MIM#130130)
• Neutropenia, severe congenital, 3, AR; SCN3 (MIM#610738); mutations in
HAX1 (MIM#605998)
• Acquired: Viral infection (common), drug-induced (common), bone marrow
failure syndrome (rare)
↓ Neutrophil Function
• Granulomatous disease, chronic, X-linked (XLR); CDGX (MIM#306400): A
primary immunodeficiency (defective microbial killing); mutations in CYBB
(MIM#300481).
• Hyper-IgE recurrent infection syndrome (HIES), AD (MIM#147060): A
primary immunodeficiency characterized by chronic eczema, recurrent
Staphylococcal infections, ↑serum IgE, and eosinophilia due to STAT3
(MIM#102582) mutations.
Disorders of MyelopoiesisMust know
AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive

2. Myelopoiesis
• Hematopoiesis: Hematopoietic multipotent (stem) cells can differentiate to →
erythrocytes, megakaryocytes, neutrophils, eosinophils, basophils, monocytes,
T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and mast cells.
• Myelopoiesis I: Multipotent (stem) cell → CFU-GEMM (CD34+/ HLA-DR+).
• Myelopoiesis II: CFU-GEMM → CFU-GM (CD34+/ HLA-DR+/ CD-64+).
– CFU-GM is driven by the growth factors c-kit ligand, IL-3, IL-6, and GM-CSF.
• Myelopoiesis III: CFU-GM → CFU-G (CD34+/ HLA-DR+/ CD-64+).
– CFU-G is driven by the growth factor G-CSF.
CFU: Colony forming units that grow at 37ºC in semisolid medium as pure colonies in 7 days.
CFU-GEMM: Colony forming units of precursor to granulocytes, erythrocytes, macrophages
(monocytes), and megakaryocytes.
CFU-GM: Colony forming units of precursor to granulocytes and monocytes/macrophages.
CFU-G: Colony forming units of precursor to granulocytes.
GM-CSF: Granulocyte-macrophage colony-stimulating factor.
G-CSF: Granulocyte colony-stimulating factor.
CFU-GEMM CFU-GM CFU-G
Reading

3. Neutrophil Function
(1) Neutrophil entrance from marrow to circulation.
(2) Rolling & tethering (adherence, mediated by selectins).
(3) Adhesion: Activated endothelial cells express
intercellular adhesion molecules (ICAM), which serve
as ligands for neutrophil β2 integrins (impaired in
‘leukocyte adhesion deficiency’, LAD).
(4) Invasion through the vascular basement
membrane with release of proteases and reactive
oxidative intermediates, destructing extracellular
matrix and allowing migration into tissue (impaired
in chronic granulomatous disease).
(5-6) Uptake of pathogens into the phagocytic vacuole with concomitant degranulation both into the
phagocytic vacuole and to the exterior (impaired in Chédiak-Higashi).
(7) Chemokines [IL-8, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory
protein (MIP)-1α, and IL-1β] recruit cells of the immune system (impaired in hyper-IgE syndrome).
(8) Extracellular traps are extrusions of chromatin and cationic bactericidal granule proteins.
Reading

4. Neutrophil Function
Chemotaxis → Motility → Adhesion→ Ingestion → Killing
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Lysis of the cytoplasmic granule (G)
against two ingested zymosan
particles (Z). The dense body of the
granule disappears from view in the
interval of 5 sec. (J Exp Med
1962;116:827)
Taxis = motion or orientation
Zymosan = a glucan of repeating glucose units found on surface of fungi.
This degranulation
process is impaired in
Chédiak-Higashi
disease
Must know

5. Neutrophil “Respiratory Burst”
Most homes have a bottle of hypochlorite (Ocl-) in the kitchen or bathroom
(Domestos, Chlorox, etc.); as advertised, these products kills all household germs.
These reactions are
impaired in chronic
granulomatous disease
(↓killing of catalase-
positive bacteria)
Chronic granulomatous disease → infections with catalase-positive organisms
(Staphylococcus aureus, Serratia marcescens, Acinetobacter anitratus, Salmonella,
Burkholderia cepacia, Aspergillus, Nocardia) → necrotizing granulomas. Initial diagnosis
is made by the oxidative burst flow cytometry test (phagocytes fail to oxidize rhodamine).
Must know
Bacterial Catalase
((catalase-positive bacteria)
H2O + ½O2

6. 6
Hyper-IgE recurrent infection syndrome (HIES), AD (MIM#147060): A primary
immunodeficiency characterized by chronic eczema, recurrent Staphylococcal
infections, ↑ serum IgE, and eosinophilia due to STAT3 (MIM#102582) mutations.
(impaired chemotaxis and cytokine production)
This patient (Malaysian) had severe, persistent atopic dermatitis (intense itching), severe
atopy (asthma and allergic rhinitis), and a recent invasive infection (right hip joint and
bone). One year ago, Staphylococcus aureus and varicella-zoster virus (VZV) infections.
He had a significant history of food allergy, such as crab and shrimps which severely
flare his skin disease.
The father has similar moderate-to-severe atopic dermatitis and allergic rhinitis. His
sister has a much milder atopic dermatitis. His maternal grandfather has asthma and
maternal aunt has atopic dermatitis.
Must know

7. Mutations in LYST (MIM#606897), which encodes a lysosomal
trafficking regulator protein
↓Neutrophil chemotaxis + ↓Degranulation → ↓Bactericidal activity
↓Platelet storage pool → Bleeding
↓Melanosomes → Albinism
7
Union of lysosomal (giant)
granules in Chédiak-Higashi
Albinism
Optional Degranulation Abnormality
Chédiak-Higashi Syndrome (CHS, OMIM#214500, AR)

8. 8
Leukocyte adhesion deficiency, type I; LAD, AR (MIM#116920)
Mutations in ITGB2 (MIM#600065; integrin, beta-2)
(recurrent bacterial infections; impaired pus formation and wound healing)
Lack of CD18/CD11 surface adhesive glycoproteins (β2 integrins) on
neutrophil membranes → neutrophilia + pyogenic infections without
pus.
Infections in a toddler with leukocyte adhesion deficiency
Optional

9. Severe Congenital Neutropenia
• Recurrent otitis, gingivitis, pneumonia, enteritis, and bacteremia in early infancy.
• Neutrophil count is <0.2 ×109/L with monocytosis, anemia, and thrombocytosis.
• Bone marrow shows neutrophil maturation arrest at the myeloblast (no mature
neutrophils).
• Patients are at risk for developing acute myelogenous leukemia (AML).
• G-CSF is effective (↑increasing neutrophil counts & ↓infections).
• Hematopoietic transplantation is the only curative therapy.
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Must know
• Neutropenia, severe congenital, 1, AD; SCN1 (MIM#202700); mutations in
ELANE (MIM#130130)
• Neutropenia, severe congenital, 3, AR; SCN3 (MIM#610738); mutations in
HAX1 (MIM#605998)

10. • Recurrent neutropenia, with a cycle period of about 21 days.
• The diagnosis is established by measuring the neutrophil count twice a
week for eight consecutive weeks.
• Supportive care includes regular dental care, prompt antibacterial
therapy as needed, and genetic counseling.
• Granulocyte colony-stimulating factor (G-CSF) is given at the nadir of
the neutrophil counts.
Note: Mutations in the elastase gene are associated with both cyclic
neutropenia and severe congenital neutropenia.
Cyclic neutropenia, AD (MIM#162800); mutations in ELANE (MIM#130130)
Must know

11. • Neutropenia due to proliferative defect and ↑apoptosis of
early myeloid progenitor cells.
• Clinical findings begins in the neonatal period and include short
stature, inadequate weight gain, skeletal abnormalities, infections
(otitis media, sinusitis, pneumonia), and large stools (steatorrhea,
malabsorption, pancreatic exocrine deficiency), and marrow
failure.
– Imaging confirms extensive fatty replacement of the pancreas.
– The presentation resembles cystic fibrosis (sweat chloride is
normal in Shwachman syndrome and high in cystic fibrosis).
• The risk of evolution to myelodysplastic syndrome and acute
myelogenous leukemia is at least 20%.
• G-CSF raises the neutrophil counts.
• Hematopoietic stem cell transplantation is curative.
11
Shwachman-Diamond Syndrome 1; SDS1, AR
(MIM#260400); mutations in SBDS (MIM#607444)
Optional

12. 1. Neutrophil respiratory burst defect + XLR +
catalase-positive pathogens
2. Giant neutrophil granules + albinism
3. Negative CD11/CD18 expression + neutrophilia
4. Eczema + infections + Stat 3 mutation
5. Pancreatic insufficiency + neutropenia + SBDS
mutation
6. Elastase gene (ELANE)
7. Risks of developing AML
8. Treatment with G-CSF
9. Hematopoietic stem cell transplantation
A. Severe congenital neutropenia
B. Shwachman-Diamond Syndrome
C. Cyclic neutropenia
D. Chronic granulomatous disease
E. Chédiak-Higashi syndrome
F. Leukocyte adhesion deficiency
G. Hyper IgE syndrome
Fever with neutropenia is best treated with monotherapy (meropenem, cefepime or
ceftazidime). Although these regimens do not cover methicillin-resistant Staphylococcus
aureus and coagulase-negative staphylococci, vancomycin should be withheld in low-risk
patients pending cultures in an effort to prevent vancomycin-resistant enterococci.
Must Know Pearls
Freifeld AG, et al. Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic
patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56-93. doi: 10.1093/cid/cir073.

13. Two brothers present to the clinic for evaluation of recurrent neutropenia. They suffer
from regular episodes of mucositis, sinusitis, otitis media, pharyngitis and tonsillitis.
Their maternal grandfather, mother, maternal aunt and her son all have neutropenia.
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0
500
1000
1500
2000
0 10 20 30 40 50
ANC
days
CBC on the 5-year-old boy reveals absolute neutrophil
count (ANC) of 300/mL (0.3 x109/L). The results of his
ANC over 45 days are shown. Blood smear shows normal
neutrophil morphology.
Which of the following is the most likely diagnosis?
A. Chédiak-Higashi syndrome
B. Leukocyte adhesion deficiency
C. Hyper IgE syndrome
D. Severe congenital neutropenia
E. Cyclic neutropenia