MYELOPROLIFERATIVE NEOPLASM Flashcards by Kyra Catedral

• Clonal hematopoietic disorders caused by genetic mutations in the
HSC

MPN

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Myeloproliferative Neoplasm results to..(3)

Expansion

Excessive production

Accumulation of mature erythrocytes, granulocytes, and platelets

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MPNs
• Predominantly______ with accelerated, subacute, or acute phases

chronic

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MPN

WHO classification into four predominant disorders:

CML - Chronic myeloid leukemia
PV - polycythemia vera
ET - essential thrombocythemia
PMF - Primary myelofibrosis

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MPNs
further subdivided:

prefibrotic/early stage

overt fibrotic stage

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• ET, PV, and PMF
- genetically related based on the presence of_____ mutation
- absence of_______
- Each presents with proliferation of one primary myeloid element

JAK2 mutation

Ph or BCR-ABL1 fusion gene

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ET
PV
PMF

Each presents with proliferation of one primary myeloid element:

Thrombocytosis
Erythrocytosis
Neutrophilia

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BCR::ABL1-POSITIVE MYELOPROLIFERATIVE
NEOPLASMS

CHRONIC MYELOID LEUKEMIA

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CML
- arises from a single genetic translocation in a pluripotential HSC
- begins with a______ phase
- progresses to an______ (untreated)
- terminates as an______

chronic clinical phase

accelerated phase in 3 to 4 years

acute leukemia..

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Chronic myeloid leukemia (CML)

• Clinical Features - FABS

frequent infection
anemia
Bleeding
splenomegaly

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CML

• Peripheral blood
-_______ all maturational stages present,_____,_______, and often______ are commonly observed in peripheral blood

Neutrophilia

basophilia

eosinophilia

thrombocytosis

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CML
- occurs at all ages: predominantly in adults age______ to______

-_______ (percentage %) of all cases of leukemia

more common in______

46 to 53

15% to 20%

men than in women

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CML

• Before______
- 5-year survival was_____(now approximately_____)

22%

90%

imatinib mesylate

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CML

• Symptoms

Fatigue

decreased tolerance of exertion

Anorexia

abdominal discomfort

weight loss

symptomatic effects from splenic enlargement

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present in proliferating HSCs and their progeny in CML.
chromosomal breakage from mutagens causes the Ph chromosome (ionizing radiation)

Philadelphia Chromosome

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CML- identified as a short chromosome 22

BY…..???

• 1960 Nowell and Hungerford

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CML

• DISCOVERED THAT- Ph chromosome is a reciprocal translocation between the long arms of chromosomes 9 and 22

1973 Rowley

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Ph chromosome is a_____ translocation between the long arms of chromosomes_____ and____

reciprocal translocation

9 and 22

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Molecular Genetics
________ translocation that produces the________has been identified in four primary molecular forms that produce three versions of the BCR-ABL1 chimeric protein

t(9;22)

BCR-ABL1 chimeric gene

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• Four BCR genes in the human genome (chromosome 22)

BCR1
BCR2
BCR3
BCR4

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Wild-type ABL1 protein (usual location on_______) - codes for_______, which exhibits normal_______

chromosome 9

p125

tyrosine kinase activity

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BCR1 gene produces_____ (expresses_________ activity)

function in the regulation of cell growth.

p160

serine and threonine kinase activity

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• The ABL1 domains that regulate the kinase activity.

SH1
SH2
SH3

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• In the case of CML

BCR-ABL1 translocation occurs next to the______ domain of the ABL1 molety..

SH3

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• Therefore: -_________ loses the ability to shut off kinase activity.. - ________enzyme continuously adds phosphate groups to tyrosine residues..

BCR-ABL1 tyrosine kinase BCR-ABL1

BCR-ABL • These pathways stimulate gene expression

• keeping the myeloid cells proliferating • Reducing differentiation • reducing adhesion of cells to BM stroma • virtually eliminating apoptosis

PERIPHERAL AND BONE MARROW - between_________- diagnosed in chronic phase - median WBC count of 38 × 10 9/L, - Anemia is usually absent -_______ is common - median platelet count of 487 × 10 9/

85% and 90% thrombocytopenia

Dexteased in PBS

LAP

Decreased in BM

Erythropoiese

Gaucher-like Green-gray crystals

Sea blue Increased

OTHER LABORATORY FINDINGS: CML • Diagnosis - demonstrating the presence of the t(9;22) translocation by _____ - detection of the BCR::ABL1 fusion gene using______ - detection of the fusion transcript by___-

cytogenetic analysis fluorescence in situ hybridization quantitative RT-PCR

PROGRESSION three stages of progression

chronic phase high-risk chronic phase blast phase

***Before imatinib,*** most cases of CML would eventually reach blast phase and transform into acute leukemia within______

3 to 4 years

In acute leukemia blasts is more than____ of total bone marrow cellularity peripheral blood exhibits increased blasts Blast phase leukemia usually is_____ or_____

20% AML (70%) or ALL (30%),

TREATMENT: CML

alkylating agents (nitrogen mustard) and busulfan Interferon-a Bone marrow transplantation (autologous or allogeneic HSCs) TKI Imatinb mesylate

Increasing the frequency of long-term patient survival, especially when combined with cytarabine.

Interferon-a

inducing the suppression of the Ph chromosome Reducing the rate of cellular progression to blast cells

Interferon-a

Optimal survival occured when the patient was ***treated during the chronic phase within 1 year of diagnosis*** and was younger than age 50

Bone marrow transplantation (autologous or allogeneic HSCs)

- Blocking the constitutive tyrosine kinase activity and reducing signal transduction activation.

TKI

- Current first-line therapy

TKI

TKI - bind the abnormal____

BCR::ABL1 protein

inhibit the tyrosine kinase activity of the BCR::ABL1 fusion protein.

Imatinib mesylate

- first synthetic TKI designed to selectively bind the ATP binding site

Imatinib mesylate

IMATINIB • Goals of therapy includes:

• complete hematologic, cytogenetic, and molecular remission • a normalized CBC and differential • absence of Ph chromosome by karyotype analysis • absence of measurable BCR::ABL1 transcripts.

is reactivation of apoptotic pathways

Complete remission

IMATINIB measure of the effectiveness: the number of log reductions of BCR::ABL1 transcripts by____

RT-PCR.

IMATINIB Limitation: development of______ resulting in relapse. Primary.- Inability to reach the remission milestones (most treatment failures) Secondary - loss of a previous response

RESISTANCE

> It is ***effective against all imatinib-resistant mutants*** (except the T315| mutation): first-line therapy imatinib therapy unless the T315l mutation has been identified

DASATINIB

> also inhibits SRC family kinases (SFK), c-kit, PDGFR, and ephrin A receptor kinase

DASATINIB

> binds the ABL1 portion of the BCRABL1 protein with an affnity similar to imatinib

DASATINIB

DASATINIB > It is effective against all imatinib-resistant mutants (except the ______| mutation): first-line therapy imatinib therapy unless the ______ mutation has been identified

T315 mutation

> Similar to dasatinib - ***rescue patients with imatinib resistance*** against all mutants currently identified (except the 315l mutation)

NILOTINIB

- a derivative of imatinib and ***binds more speciffcally than imatinib to ABL1,*** stabilizing the ABL1 protein.

NILOTINIB

> binds to the ATP binding site of the ABL1 protein in the inactive conformation with ***30x greater potency than imatinib***

NILOTINIB

NILOTINIB Similar to dasatinib - rescue patients with imatinib resistance against all mutants currently identified (except the_______ mutation)

T315l

> It inhibits ABL1 and SRC kinases, FGFR, and MAPK > does not signiffcantly inhibit PDGFR or c-kit.

BOSUTINIB

> binds both the active and the inactive conformations of ABL1 and is ***10 times more potent than imatinib.***

BOSUTINIB

rescue about 70% of patients who developed the T3151 mutation in response to first- and second-generation TKI therapy.

PONATINIB

• rescue therapy for patients ***resistant to imatinib, dasatinib, and nilotinib***

PONATINIB

> a plant alkaloid that induces apoptosis, inhibits protein synthesis, and upregulates BAX and PARP

HOMOHARRINGTONE

> supplemental therapy to TKIs (rescue patients who developed TKI resistance)

HOMOHARRINGTONE

> originally discovered and used for CML therapy before the development of TKls.

HOMOHARRINGTONE

> ***semisynthetic derivative of homoharringtonine*** • induce apoptosis but by downregulating myeloid cell leukemia sequence-1 Mcl-1

OMACETAXINE

> administered as SQ injection twice daily for 14 days of a 28-day cycle: induction phase: followed by 7 days of a 28-day cycle: maintenance

OMACETAXINE

BCR::ABL1- ***NEGATIVE*** MYELOPROLIFERATIVE NEOPLASMS > It is composed mainly of 3 specific disorders: > between______ to _____ years of age.

ET, PV, and primary myelofibrosis (PMF) 53 and 64

> increase in one or more myeloid cells lines (platelets, erythrocytes, myelocytes): morphologically and functionally normal

BCR::ABL1-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS

- initially presents with a leukocytosis and a left shift - slowly develops fibrosis in the bone marrow that inhibits hematopolesis - eventually resulting in pancytopenia

PMF

- must present with erythrocytosis but also shows leukocytosis

- thrombocytosis but can also exhibit leukocytosis and a left shift

MOLECULAR PATHOPHYSIOLOGY: ET, PV, PMF • share three common gain-of-function driver mutations:

• JAK2 (JAK2 V617F) • calreticulin (CALR) • myeloproliferative leukemia virus oncogene (MPL) "thrombopoietin receptor"(TPOR)

- constitutive activation of the thrombopoietic receptor (TPOR or MPL) - activation of the______ signaling pathway. - may occur years before symptom onset (childhood and infancy) - driver mutations in the HSCs - accumulation of mutated HSCs

JAK2

JAK2 - has 7 domains (______): two domains (_____) control the kinase activity.

JH1 through JH7 JH1 and JH2

- closely associated with cytokine receptors EPO, TPO, and G-CSF - controls transphosphorylation through conformational inhibition

• JAK2 protein

- is a tyrosine kinase enzyme much like the ABL1 moiety of the BCR::ABL1 fusion gene found in CML

JAK2 protein

> cytokine receptor binds its ligand > activates JAK2 protein (transphosphorylation) - bound to the cytoplasmic region of the receptor

- the most common JAK2 mutation - 95% of patients with PV and is found on chromosome band 9p24.

JAK2 V617F

> conformational change in the EPO receptor - dimerization of 2 EPO ›This produces a docking point for the head of the inactive JAK2 protein at the FERM > Docking of JAK2 stimulates a phosphorylation event, causing a conformational change, •and the valine releases from the pseudokinase domain

JAK2 V617F

>HSCs that bear the_____ mutation are ***resistant to erythropoietin-deprivation apoptosis***

JAK2

- activation of several signal transduction pathways that are (normally activated after EPO stimulation) is active and will phosphorylate STAT proteins in the absence of erythropoietin or will over phosphorylate in its presence

• mutated JAK2 protein

DISEASE PROGRESSION • ET - progress to____ • either ET or PV - to____ • MPN-CP - MPN-BP or to an overt_____ • driver mutations (JAK2, MPL, and CALR) - lesser role in disease progression • triple-negative PV patients (negative for JAK2, MPL, and CALR) - greater risk of leukemic transformation than PV patients with a high JAK2 allele burden.

PV sMF acute leukemia.

MYELOPROLIFERATIVE NEOPLASM Flashcards

(80 cards)