Myeloid Neoplasms Flashcards
What are the two types of hematopoietic neoplasms?
- Myeloid neoplasms
- Lymphoid neoplasms
List the three important myeloid neoplasms
- Acute Myeloid Leukemia (AML)
- Myeloproliferative Neoplasms (MPN)
- Myelodysplastic Syndroms (MDS)
For Myeloid Neoplasms, list:
- two common features
- where they generally arise
- description of the group of disorders
- monoclonal, origin from HSCs or progenitor cells
- generally arise in bone marrow
- very heterogenous** **group of disorders, with considerable overlap
From the common myeloid progenitor, list the 4 types of cells it gives rise to
- Megakaryocyte
- Erythrocyte
- Mast cell
- Myeloblast
List the 4 cells a myeloblast gives rise to
- basophil
- neutrophil
- eosinophil
- monocytes –> macrophage
What makes up the bone marrow stroma? List two important functions
Bone marrow stroma:
stromal cells, ECM molecules, reticulin framework
- Provides a scaffold onto which the developing cells are bound
- helps direct traffic of the cytokines that regulate hematopoiesis
For AML, list the following:
- type of problem
- what you see as a result
- acute or chronic
AML:
- problem of differentiation AND proliferation
- high WBC (blasts) or pancytopenia (decreased count)
- acute
For MPN, list the following:
- type of problem
- what you see as a result
- acute or chronic
MPN:
- problem of proliferation (they have no problem maturing and differentiating)
- leukocytosis, erythrocytosis, thrombocytosis (increased count)
- chronic
For MDS (Myelodysplastic Syndrome), list the following:
- type of problem
- what you see as a result
- acute or chronic
MDS:
- Problem of differentiation (abnormal maturation, ineffective hematopoiesis)
- cytopenias, pancytopenia
- chronic
Myeloid neoplasms, like other malignancies, tend to evolve over time to more aggressive forms of disease. For example, CML can transform to acute lymphoblastic leukemia. What does this indicate?
Indicates that the CML originated from a transformed pluripotent hematopoietic stem cell
- definition of AML
- cause of AML
- effect on cells
- neoplasm of hematopoietic progenitors
- cause: acquired genetic abnormalities (somatic mutation) that interfere with proliferation and differentiation
- accumulation of blasts in the marrow, resulting in marrow failure
- anemia, neutropenia, and thrombocytopenia
3 main ways AML arises
- De novo: in absence of risk factors
- AML arising with pre-existing genetic factors
* Fanconi’s anemia, Down’s, Kostmann syndrome, Wiskott Aldrich syndrome, Li-Fraumeni syndrome - AML arising after certain exposures
- radiation
- toxic chemicals
- therapy related: chemo (topoisomerase II inhibitors, alkylating agents), radiation therapy
Describe the acute presentation of AML and relate the characteristics to clinical signs
- ill patient for weeks/few months
- symptoms related to bone marrow failure:
- anemia: fatigue
- neutropenia: infection, fever (opportunistic–fungi, pseudomonas)
- thrombocytopenia: spontaneous bleeding
- bone pain
DIC presents in AML. Which particular type is most common?
AML t(15;17)
chloroma (myeloid sarcoma)
AML occasionally presents as such: a localized soft-tissue mass
Extra-medullary involvement of AML
AML with monocytic differentiation often infiltrate the skin (leukemia cutis) and gingiva)
Lab abnormalities in AML:
CBC:
- number of blasts in blood is highly variable
- increase WBC with numerous blasts (leukostasis)
- decreased WBC (leukoenia) /// pancytopenia
- very few circulating blasts, but marrow packed with blasts
Other lab abnormalities:
- increase in uric acid (reflection of high cell turnover)
explain the molecular pathogenesis of AML t(8;21)
example of a somatic mutation in transcription factors required for normal myeloid differentiation (maturation):
- disruption of CBFa (RUNX1) gene
- normally encodes a protein that binds another protein to form a TF needed for normal hematopoiesis
- t(8;21) creates a chimeric gene BLOCKS the maturation of myeloid cells
Tyrosine kinases:
- normal role
- what happens in AML
- example mutation
- involved in regulation of cell survival and proliferation
- AML: activating mutations lead to INCREASED proliferation
- example: FLT3 mutations
List the genetic alterations in AML that are **Class 1 Proliferation **(5)
- FLT3
- KIT
- RAS
- PTPN11
- JAK2
Genetic alterations in AML-Class II Differentiation (5)
- PML-RARA
- RUNX-RUNX1t1
- CBFB-MYH11
- MLL fusions
- CEBPA
How do we diagnose AML? (3)
- Morphology (microscopic examination of blood and bone marrow)
- Immunophenotyping
- Cytogenetics/Molecular Genetics
Two types of immunophenotyping
Flow cytometry, immunohistochemistry
(FC is good for leukemias vs carcinomas since dealing with wet specimans//cells floating in suspension, vs. solid tumors
3 types of cytogenetics/molecular genetics
Karyotype, FISH, PCR
AML definition: % blasts
blasts > or = to 20% in blood or bone marrow
(blast count can be lower in some AML defining translocations, i.e. 8;21 and 15;17
in AML, describe how blasts are heterogenous in appearance
myeloblasts, monoblasts, with/without Auer rods
What are auer rods, and what are they indicative of
Aurer rods are crystal aggregates of MPO. They are sometimes seen in acute myelogenous leukemia
(myeloblasts are usually characterized by positive cytoplasmic staining for myelopoeroxidase)
In flow cytometry, what are 5 myeloid-specific antigens?
- CD13
- CD33
- CD117
- CD11b, CD11c
- MPO
What are the 4 main categories of AML classification?
- AML associated with particular genetic abberations
e.g. t(8;21), inv(16), t(15;17), better prognosis - AML arising after a myelodysplastic disorder, or with MDS- like features: usually poor prognosis
- Therapy-related AML
- AML, NOS (not otherwise specified): “Wastebasket: category
AMLs lacking any of these features, classified based on
differentiation and lineage
t(15;17)
what gene gets affected
**Acute promyelocytic leukemia **
example of an AML with recurrent genetic abnormality
involves translocations of the retinoic acid receptor (RAR): results in PML/RARA fusion gene
RAR disruption blocks maturation and promyelocytes (blasts) accumulate
Why is AML with t(15;17) a medical emergency
Abnormal promyelocytes (blasts) that build up contain numerous primary granules that increase the risk of DIC
treatment of acute promyelocytic leukemia t(15;17)
all-trans-retinoic acid (ATRA)
a vitamin A derivative, binds the altered receptor and causes the blasts to mature into neutrophils
List the 5 main myeloproliferative neoplasms
- Chronic Myelogenous Leukemia
- Polycythemia Vera
- Essential Thrombocytosis
- Primary Myelofibrosis
- Systemic Mastocytosis
tyrosine kinases in Myeloproliferative Neoplasms
constitutively activated: they bypass normal controls and lead to growth factor INDEPENDENT proliferation
thus: this is a problem with proliferation–differentiation is intact
What do you see in the peripheral blood in Chronic Myelogenous Leukemia?
Leukocytosis with left shift (expansion of white cell precursors)
- neutrophilia, basophilia, and/or eosinophili
- often anemia and thrombocytosis
Aside from the peripheral blood abnormalities, what are two other important findings in CML?
Bone Marrow: hypercellular bone marrow with maturation
Splenomegaly: enlarging spleen suggests progression to accelerated phase of disease
What type of mutation drives Chronic Myeloid Leukemia?
Driven by t(9;22) Philadelphia Chromosome, which generates a BCR-ABL fusion protein with increased tyrosine kinase activity
Chronic myeloid leukemia is neoplastic proliferation of mature myeloid cells. Which cells in particular are characteristically increased?
granulocytes and their precuroses; BASOPHILS
What do you expect to see in a bone marrow biopsy of CML?
You will see a packed marrow filled with cells, but the key thing is you will see a MIXTURE of cells. This is because the cells are still differentiating (unlike in acute myeloid leukemia); there is just abnormal proliferation
blast crisis in CML
natural history of CML:
chronic phase (3 years) –> accelerated phase (count starts to deteriorate) –> blast crisis (months)
blast crissi is CML that transforms to acute leukemia (AML or ALL)
*MPNs may originate in multipotent myeloid progenitors that give rise to a pure myeloid process, or in pluripotent hematopoietic stem cells that give rise to both lymphoid and myeloid cells
It is unlikely that CML will progress to blast crisis, because the disease is well controlled. What are the 5 important treatments?
hydroxyurea
interferon +/- cytosine arabinoside
Allogeneic bone marrow transplant
Imatinib mesylate (tyrosine kinase inhibitor)
dasatinib, nilotinib (second generation TKI)
Polycythemia vera:
- what is the problem
- what is the mutation type
- neoplastic proliferation of mature myeloid cells, especially RBCs
- associated with JAK2 kinase mutation: JAK2 participates in JAK/STAT pathway, which lies downstream of multiple hematopoietic growth factor receptors, including EPO receptor
clinical symptoms of polycythemia vera:
due to hyperviscosity of blood (from high red blood cell count!)
- blurry vision and headache
- increased risk of venous thrombosis (hepatic vein, portal vein, and dural sinus)
- flushed face due to congestion
- itching after bathing (histamine release from increased mast cells)
How can you distinguish polycythemia vera from reactive polycythemia?
EPO
PV: low EPO (negative feedback); SaO2 normal
Reactive polycythemia: high EPO (due to high altitude or lung disease); SaO2 is low
also see high EPO in tumor i.e. renal cell carcinoma
Essential Thrombocythemia
- what is the problem
- associated with what type of mutation
- neoplastic proliferation of mature myeloid cells, especially platelets
- associated with a JAK2 kinase mutation
Symptoms in Essential Thrombocythemia
related to an increased risk of bleeding (platelets not functioning) and/or thrombosis (platelets overfunctioning):
-rarely progresses to marrow fibrosis or acute leukemia
Why is there no sigfnicant risk for hyperuricemia or gout in Essential Thrombocythemia?
Hyperuricemia or gout is associated with high cell turnover; in ET, you don’t have excess turnover- just pieces of cytolasm blebbing off for platelets.
Compare the following for PV and ET:
- increase primarily in
- splenomegaly
- myelofibrosis potential
- AML transformation
PV:
- increase primarily in RBCs
- splenomegaly** COMMON**
- myelofibrosis potential** 15-20%**
- AML transformation uncommon
ET:
- increase primarily in** PLATELETS**
- splenomegaly **in minority **
- myelofibrosis potential is **infrequent **
- AML transformation
PV:
- increase primarily in RBCs
- splenomegaly COMMON
- myelofibrosis potential 15-20%
- AML transformation **is uncommon **
Post-polycythemic myelofibrosis (spent phase): 3 main characteristics
- overt bone marrow fibrosis: reticular fibers
- worsening splenomegaly due to extramedullary hematopoiesis
- leukoerythroblastic blood smear (tear drop RBCs, nucleated RBCs, and immature granulocytes
Primary myelofibrosis
- problem
- mutation
- neoplastic proliferation of mature myeloid cells, especially megakaryocytes
- JAK2 kinase mutation (50%); MP mutation (1-5%)
For each Myeloproliferative Neoplasm, list the mutation:
1) CML
2) P vera
3) Essential Thrombocythemia
4) Primary Myelofibrosis
1) CML: BCR/ABL
2) P vera: JAK2 V617F or other JAK2 mutation
3) ET: JAK2, MPL, or Calreticulin
4) Primary Myelofibrosis: JAK2, MPL, or Calreticulin
most of these are tyrosine kinase pathways
5 key points of myeloproliferative neoplasms
1) PROLIFERATION: increased proliferative drive in bone marrow : results in high WBC count with hypercellular bone marrow
2) EXTRAMEDULLARY HEMATOPOIESIS
3) TRANSFORMATION TO SPENT PHASE: bone marrow fibrosis and peripheral blood cytopenias
4) VARIABLE TRANSFORMATION TO ACUTE LEUKEMIA
5) MOLECULAR TESTS FO RTYROSINE KINASE MUTATIONS: important for diagnosis and the selection therapy; availability of kinase inhibitors
Most common hematologic malignancy in the elderly
Myelodysplastic Syndromes (MDS)
What is Myelodysplastic Syndrome? (4)
- Clonal stem cell disorder
- abnormal maturation (uni or multi lineage dysplasia)
- ineffective hematopoiesis resulting in cytopenias
- Susceptibility to leukemic transformation (AML)
Explain the ineffect hematopoiesis that occurs in myelodysplastic syndrome
- the clonal stem cells can differentiate, but in an ineffective manner
- the abnormal maturing cells accumulate in the bone marrow, partly or completely replacing normal hematopoiesis
- resulting in anemia, leukopenia, and/or thrombocytopenia
Pathogenesis of MDS: 4 genetic abnormalities
1) Epigenetic factors: mutations that regulate DNA methylation and histone modifications; similar to AML mutations
2) RNA splicing factors: mutations involving the 3’ end of RNA splicing machinery
3) TFs: mutations in ones needed for normal myeloid differentiation
4) Tumor suppressor gene TP53 in 10% of MDS cases
Tyrosine kinases in MDS
activatin mutations in Tks are NEARLY ABSENT IN MDS!!! (unlike in AML and MPNs)
3 clinical features of MDS:
1) disease of older adults: present with fatigue and mild anemia
2) discovered incidentally on routine blood testing
3) cytopenias resulting in weakness, infections, and hemorrhages
5q- syndrome
specific subtype of MDS:
- resulting in ineffective erythropoiesis
- occurs more often in elderly woman
- macrocytic anemia and thrombocytosis (high platelet count)
What must you do when diagnosing MDS?
you MUST rule out other disorders i.e. check serum B12, RBC folate, serum iron, TSH, copper levels
Characteristic morphologic changes in bone marrow and peripheral blood in MDS:
- abnormal bi-lobed pelger huet-like neutrophil
- hypogranular neutrophil
- erythroid dysplasia
MDS treatment
- supportive: transfusions, antibiotics
- MDS is particularly resistant to conventional chemo
- DNA methylation inhibitors
- Thalidomide-like drugs: Lenalidomide in 5q syndrome
- allogenic HSC transplantation (young pts)
clonal multipotent stem cell that can differentiate but in an ineffective manner
MDS
Molecular pathogenesis of MDS:
increased apoptotic cell death
Does MDS progress to AML?
YES, often
