myeloproliferative neoplasms

Question 1

MPNs is defined as unregulated cell proliferation and survival due to dysregulated _______ or its associated signal transduction

Answer 1

tyrosine kinase

Question 2

two important tyrosine kinase mutations associated

1. ________ and _________oncogene in CML
2. _________ up-regulation in p. vera, ET and MF

Answer 2

1. philadelphia chromosome and BCR-ABL1 oncogene in CML

2. JAK2 up-regulation in p. vera, ET and MF

Question 3

positive philadelphia chromosome

Answer 3

chronic myleogenous leukemia

Question 4

chronic myleogenous leukemia

Answer 4

slowly progressing blood and bone marrow disease that usually occurs during or after middle age and rarely occurs in children and with presence of philadelphia chromosome

Question 5

CML:

1. slightly higher in males or females
2. risk factors
3. what would be expected to find in lab?
4. 50% are asymptomatic with suspicion based on labs but we could expect to see what symptoms?
5. why do we see heapot-splenomegaly?

Answer 5

1. slightly higher in males
2. risk factors include ionizing radiation and maybe post chemo
3. lab should show an increased WBC count (leukocytosis), mild anemia and either a normal or elevated platelet count
4. excess cytokiness could lead to fatigue, malaise and bleeding dysfunction due to platelet dysfunction
5. due to other organs starting to compensate for BM and generate cells called extramedullary hematopoiesis

Question 6

CML clinical hallmark is uncontrolled production of __________ cells of the neutrophil lineage with disease progression in triphasic phases .

these phases are:

1. chronic phase where there is an increase in committed myeloid progenitors leading to _____ and _____
2. Accelerated phase there is increase ____cells in the peripheral blood smear with _____and an _______ WBC count. there is a need for more intensive myelosuppressive therapy
3. Blast crisis- blasts cells are over 20% thus this phase resembles _____

Answer 6

CML clinical hallmark is uncontrolled production of maturing myeloid cells of the neutrophil lineage with disease progression in triphasic phases .

these phases are:

1. chronic phase where there is an increase in committed myeloid progenitors leading to leukocytosis and thrombocytosis
2. Accelerated phase there is increase blast cells in the peripheral blood smear with splenomegaly an increasing WBC count. there is a need for more intensive myelosuppressive therapy
3. Blast crisis- blasts cells are over 20% thus this phase resembles AML

Question 7

cytoplasmic constitutively active tyrosine kinase

Answer 7

BCT-ABL1

Question 8

what is a non-diagnostic finding but a prognostic finding for CML

Answer 8

granulocytic hyperplasia from a BM aspiration in patients with CML in chronic phase

Question 9

causes of Imatinib resistance :

1. point mutation in the _____kinase domain
2. amplification of _____gene
3. medication non-compliance

Answer 9

1. point mutation in the ABL1 kinase domain
2. amplification of ABL1 gene
3. medication non-compliance

Question 10

role of allogenic stem cell transplantation

Answer 10

Pre-TKI it was the only known curative treatment but there were many cases of graft failure vs host that decreased overall survival

Now, it is done post- TKI where, TKI serve a a bridge

Question 11

Ph-negative myeloproliferative neoplasms are (3)

and the cardinal feature is the dysregulated activation of _________signal transduction pathway

Answer 11

1. polycythemia Vera
2. essential thrombocytosis
3. primary myelofribrosis

and the cardinal feature is the dysregulated activation of Jak-STAT signal transduction pathway

Question 12

Important for cytokine and growth factor signaling
Transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell.

Answer 12

JAK-STAT pathway

Question 13

which drug is active against T3151 mutation

Answer 13

posatinib

Question 14

codes for a tyrosine kinase (JAK2) that is associated with the cytoplasmic portion of a variety of transmembrane cytokine and growth factor receptors

Answer 14

Janus Kinase 2 Gene:

Question 15

codes for thrombopoietin receptor

____Exon 10 mutation

Answer 15

Myeloproliverative leukemia virus oncogene (MPL

Question 16

encodes for the protein, calreticulin, is a second messenger during signal transduction
_______exon 9 mutation: mainly activate MPL and at a low level the G-CSFR but not the EPOR,explaining the thrombocytosis associated with these mutants

Answer 16

CALR

Question 17

a disease in which too many RBC are made in the Bone marrow

Answer 17

polycythemia Vera

Question 18

polycythemia Vera:

1. pathogenesis: autonomous – ?
2. presentation- ?
3. lab: includes____________ HCT/HGB/RBC# and RBC mass, platelets > 400k, WBC > 12,000, BM is ______ with __________ Fe storage and __________ serum Epo

Answer 18

1. pathogenesis: autonomous – Epo or erythropoietin independent erythropoiesis
2. presentation- hepatosplenomagly
3. lab: includes elevated HCT/HGB/RBC# and RBC mass, platelets > 400k, WBC > 12,000, BM is hypercellular with absent Fe storage and decreased serum Epo

Question 19

polycythemia Vera the EPO receptor is activated constitutively due to lack of auto-inhibition of the ______ enzyme probably due to the presence of an activating mutation involving an amino acid substitution of __________

Answer 19

polycythemia Vera the EPO receptor is activated constitutively due to lack of auto-inhibition of the JAK2 enzyme probably due to the presence of an activating mutation involving an amino acid substitution of valine to phenylalanine (V617F)

Question 20

diagnosis of P. Vera requries 3 major criteria or the first 2 major criteria and the minor criterion:

a. major criteria
(1) Hgb is ?
(2) BM is _______ with proliferation of mature myeloid cell line
(3) presence of ______

b. Minor criteria
(1) serum Epo is ______

Answer 20

a. major criteria
(1) Hgb is > 16.5
(2) BM is hypercellular with proliferation of mature myeloid cell line
(3) presence of JAK-2

b. Minor criteria
(1) serum Epo is decreased

Question 21

prognosis and treatment of P.Vera

1. prognosis in untreated is _______and in treated it is ________
2. adverse events include _________ due to hyperviscosity from increased counts and progression of disease to either ____ or _______
3. treatment goal is to reduce Hct to ________. other treatments include a new inhibitor that blocks
   _____ and _____that normalizes Hct and reduce JAK2 levels. Adding _________might be a good idea for elderly or refractory patients

Answer 21

1. prognosis in untreated is months and in treated it is years
2. adverse events include thrombosis due to hyperviscosity from increased counts and progression of disease to either myelofibrosis or AML
3. treatment goal is to reduce Hct to <45%. other treatments include a new inhibitor that blocks JAK2 and IFN alpha that normalizes Hct and reduce JAK2 levels. Adding hydroxyurea might be a good idea for elderly or refractory patients

Question 22

presence of an abnormal increase in the number of platelets made in the bone marrow and circulate in the blood

Answer 22

essential thrombocytopenia

Question 23

essential thrombocytopenia requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion:

a. major criteria
1. _____ platelets count
2. BM showing proliferation of enlarged mature __________
3. not meeting any criteria of other________
4. mutation in either (3) mutation

b. minor criteria
1. presence of _______ marker
2. absence of evidence of reactive _____________

Answer 23

a. major criteria
1. elevated platelets count
2. BM showing proliferation of enlarged mature megakaryocytes
3. not meeting any criteria of other MPNs
4. mutation in either JAK2, CALR or MPL mutation

b. minor criteria
1. presence of clonal marker
2. absence of evidence of reactive thrombocytosis

Question 24

cant confuse essential thrombocytosis from secondary thrombocytiosis conditions such as iron-deficiency anemia , hemolytic anemia, absence of spleen or from more acute causes like blood loss, infection, physical activity

Answer 24

yep

Question 25

essential thrombocytosis treatments:

1. low risk-
   _________
2. intermediate/high risk– (2)
3. addition of ________ is beneficial for patients who are older in preventing thrombotic events

Answer 25

1. low risk- no treatment
2. intermediate/high risk– (1) hydroxurea (2)anagrelide
3. addition of aspirin is beneficial for patients who are older in preventing thrombotic events

Question 26

a disease in which abnormal blood cells and fibers build up inside the bone marrow

Answer 26

primary myelofibrosis

Question 27

teardrop cells in peripheral blood smear

Answer 27

primary myelofibrosis

Question 28

in primary myelofibrosis results of BM biopsy show megakaryocyte proliferation and atypia with evidence of

Answer 28

in primary myelofibrosis results of BM biopsy show megakaryocyte proliferation and atypia with evidence of reticulin fibrosis

Question 29

primary myelofibrosis:

1. pathogenesis- ____________ secondary to secreted GF
2. patients have the _______ mutation in about 30-50%
3. some cases evolve from pre-existing _______ or ______

Answer 29

1. pathogenesis- nonclonal BM fibroblast proliferation secondary to secreted GF
2. patients have the JAK2 mutation in about 30-50%
3. some cases evolve from pre-existing PV or ET

Question 30

primary myelofibrosis: requires all three major criteria and one minor criterion:

a. major:
1. presence of _________ proliferation with __________ fibrosis
2. not meeting criteria for _________
3. mutations in either __________

b. minor:
1. leukocytosis
2. __________ serum level of lactate dehydrogenase
3. anemia
4. palpable splenomegaly

Answer 30

a. major:
1. presence of megakaryocyte proliferation with reticulin /collagen fibrosis
2. not meeting criteria for P. Vera, CML or other MPN’s
3. mutations in either JAK2, CALR or MPL

b. minor:
1. leukocytosis
2. increased serum level of lactate dehydrogenase
3. anemia
4. palpable splenomegaly

Question 31

primary myelofibrosis:

1. presentation- massive _________ due to extramdeullary hematopoiesis
2. lab should show anemia and BM asp. that is dry ,meaning there is a lot of ________. about 30-50% should have a __________ abnl. such as 13q- and 20q-
3. prognosis is_________with overall survival of 3 yr.
4. which mutation is associated with a more indolent clinical course-
5. only curative treatment is
6. supportive therapy for _________such as Epo, ________ for constitutional symptoms, _________for pain and transfusion dependent anemia or _______ inhibitors for reduction in spleen

Answer 31

1. presentation- massive spleenomegaly due to extramdeullary hematopoiesis
2. lab should show anemia and BM asp. that is dry ,meaning there is a lot of fibrosis. aabout 30-50% should have a clonal cytogenetic abnl. such as 13q- and 20q-
3. prognosis is poor with overall survival of 3 yr.
4. which mutation is associated with a more indolent clinical course- calreticulin gene
5. only curative treatment is allogeneic HSCT
6. supportive therapy for anemia such as Epo, chemo for constitutional symptoms, splenectomy for pain and transfusion dependent anemia or JAK2 inhibitors for reduction in spleen

Question 32

shrink spleen and improve constitutional symptoms and quality of life

Answer 32

JAK2 inhibitor