Myeloproliferative disorders and leukemia Flashcards
1
Q
Stem cells
A
- Can self-renew (by dividing into 2 stem cells or 1 stem cell and 1 progenitor)
- Can differentiate into more mature cells (by dividing into 1 stem cell and 1 progenitor, or dividing into 2 progenitors)
2
Q
Myeloproliferative disorders
A
- Are acquired clonal hematopoietic SC disorders (the source is a single mutated cell- the rest are clones of it)
- Can be variable effects on differentiation of the myeloid progenitors
3
Q
Ways to identify clonality
A
- Look at genetic or molecular changes (will be found in all clonal cells)
- XCIP: random inactivation of X chrom in females by looking at X-linked proteins (G6PD) to see if its far from 50/50
- Surface Ag expression: K:L expression on B cells should be 2:1 ratio
4
Q
Chronic myeloid leukemia (CML)
A
- Most common myeloproliferative disease
- Associated w/ Philadelphia chromosome t(9,22), the first model of molecular targeting for cancer Rx
- The t(9;22) translocation moves the BCR gene (22) to the ABL gene (9) creating a Bcr-Abl fusion (chimeric) protein
- The Abl normally is a tyrosine kinase, but the fusion protein renders the kinase constitutively active
- This causes increased signaling and proliferation
5
Q
Ways to Dx CML
A
-FISH will show if there are translocations, so if you test for chrom 9 and 22 and the two fluorescent dots are right next to each other
6
Q
Phases of CML
A
- In the chronic phase of CML the pt has a normal Hb and plt count but a high WBC (these WBCs are mature granulocytes, mostly PMNs but w/ high than normal neutrophils)
- At some point the chronic phase will turn in an acute, blast phase
- The blast phase occurs when additional mutations accumulate in precursor cells and lead to blasts that are unable to further differentiate
- The blast phase can be either acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL)
7
Q
Differences btwn chronic and blast phase CML
A
- Chronic phase: myeloproliferative disease, mainly in granulocytes, last yeast, present w/ splenomegaly, leukocytosis, Hb and plts usually normal
- Blast phase: transform into acute myeloid (70%) or acute lymphoid (30%) leukemia, fatal in weeks-months if not treated, poor response to standard AML/ALL Rx, present w/ anemia and thrombocytopenia
8
Q
CML Rx
A
- Allogenic HSC Tx the only cure
- Non-specific cytotoxic CRx: hydroxyurea, cytarabine
- Targetted Rx: block the signal of the tyrosine kinase chimeric protein (bcr-abl) by imantinib (gleevec)
9
Q
Polycythemia vera (PV)
A
- Acquired clonal hematopoietic stem cell disorder characterized by elevated RBC mass/Hb
- Is a myeloproliferative neoplasm (MPN)
- Variable degree of leukocytosis and thrombocytosis
- EPO is suppressed
- Present w/ splenomegaly
- Venous and arterial thrombosis is major morbidity
- Often report: “itching after bathing”
10
Q
PV molecular mechanism
A
- Abnormal constitutive activation of JAK2
- JAK is a normal signal tyr kinase that is activated upon the binding of EPO or TPO
- In PV the constitutive activation of JAK leads to upregulation of its activity in myeloid precursors
- The signal from JAK induces growth of the cell, thus increasing the Hb
- In response the kidneys stop producing and releasing EPO
- But JAK2 isn’t the only cause of the disease, and an earlier mutation (TET2) may increase the chance of developing a JAK2 mutation
11
Q
Causes of erythrocytosis
A
- Primary causes: PV, congenital EPO receptor anomalies
- Secondary causes: mutations resulting in increased EPO (VHL, HIF2a, PHD), 2,3 DPG deficiency, high-affinity Hb, hypoxia, renal EPO-overproduction, EPO-producing tumors
12
Q
PV Dx criteria
A
- 1 major + 2 minor or 2 major + 1 minor
- Major: high Hb, JAK2 mutation
- Minor: BM trilineage hyperplasia, suppressed EPO, spontaneous endogenous erythroid colonies (EEC)
13
Q
PV clinical course
A
- Asymptomatic from mo-yrs w/ increase RBC mass (Hb/Hct)
- Then develop hyper viscosity symptoms (controlled w/ periodic phlebotomy)
- Then leukocytosis/thrombocytosis: at risk of thrombosis and may need cytoreductive Rx
- Progression to myelofibrosis after 15-20 yrs (develop anemia, progressive splenomegaly)
- Progression to acute leukemia after 20 yrs
14
Q
Essential thrombocytosis (ET)
A
- Chronic condition characterized by elevated plt counts (MPN)
- Must rule out secondary causes: infectious + inflammatory disorders, malignancy (all from increased IL6-> increased TPO, or from increase in megs), Fe deficiency
- 50% harbor JAK2 or cMPL mutation
- Major complication: arterial and venous thrombosis
- Lower rate of transformation to myelofibrosis and/or acute leukemia (10%)
- Can see fluffy megs in clusters in the BM
15
Q
Myelofibrosis (MF)
A
- Can be primary or a late complication of PV/ET
- Is a MPN
- 30-50% harbor JAK2 mutations
- Patients usually have progressive splenomegaly (“biggest spleen you will ever palpate”)
- Anemia often progressive, transfusion-dependence common
- Shortened life span (unlike ET/PV)
- Allogenic HSC Tx only cure but high morbidity and mortality
16
Q
Pathology of MF in PBS and BM
A
- PBS: Can see early myeloid cells, and nucleated RBCs
- PBS: Most distinctive is the tear-drop RBCs
- BM: can stain w/ reticulin to look at the fibrosis, will appear black
17
Q
Leukemogenesis
A
- 2 things lead to acute leukemogenesis: differentiation block and enhanced proliferation
- Differentiation block due to LOF of transcription factors needed for differentiation
- Enhanced proliferation due to GOF mutations of tyr kinases
18
Q
Acute vs chronic leukemias
A
- Acute: rapid onset (days-weeks), due to malignant clonal event and a block of differentiation
- Have an increase in immature (blast) cells that do not differentiate or mature
- Chronic leukemia: chronic onset (months-years), due to malignant clonal event w/o block of differentiation
- Leads to increase number of mature cells that do not die or undergo apoptosis
- Both acute and chronic can manifest as lymphoproliferative or myeloproliferative forms
