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Heme > Molecular Basis Of Leukemia > Flashcards

Molecular Basis Of Leukemia Flashcards

0
Q

Chronic characteristics

A
  • Liquid cancer state
  • no clear blockage (can occur at any point)
  • danger is that it can become acute
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1
Q

Acute leukemia characteristics

A
  • liquid cancer state
  • blasts accumulate
  • blasts progeny of single clone
  • abnormalities in chromosome number and structure
  • clonal cells push out all the others resulting in eventual pancytopenia
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2
Q

Lymphomas

A
  • solid tumors
  • hodgkins (Reed-steinberg cells) vs. non-hodgkins
  • cell type and aggressiveness are key factors in prognosis
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3
Q

MPDs conditions (4)

A
  • CML: granulocytes
  • Polycythemia Vera: erythrocytes
  • essential thrombocytopenia: platelets
  • Agnogenic myeloid metaplasia: BM fibros
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4
Q

MPDs lab findings

A
  • marrow hyperplasia/hyper metabolism
  • cytogenic abnormalities
  • abnormal maturation
  • lots of over lab in lab findings of MPDs
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5
Q

CML translocation and protein

A
  • 9/22 (Philadelphia)

- bcr/abl

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6
Q

AML Translocation and protein abnormality

A
  • 8/21

- AML1/ETO

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7
Q

APL Translocation and protein abnormality

A
  • 15/17

- RAR-a

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8
Q

Burkittes lymphoma Translocation and protein abnormalities

A
  • 8/14

- Ig/MYC

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9
Q

Philadelphia chromosome

A
  • 9/22 chromosomal translocation fund in 95 % CMLs
  • amplification of tyrosine kinase ABL
  • CML produces “full house” morphology
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10
Q

8/12 Chromosomal translocation

A
  • Implicated in AML

- AML1/ETO protein, complexes with CBFB normally but also complexes with co-repressor halting differentiation

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11
Q

15/17 Chromosomal translocation

A
  • Associated with APL
  • RAR-a (vitamin A)
  • inhibits at promylocytic stage
  • vitamin A binds and inhibits: deficiency can cause it, all trans retinol can trt
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12
Q

8/14 Chromosomal translocation

A
  • associated with burkitts lymphoma
  • MYC/Ig: massive proliferation (MYC is a powerful txn factor) of Ig
  • blood gets sludgy-> co-morbidities
  • not actually chimeric
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13
Q

MPO assay

A
  • hypergranular promyelocytes
  • aure rods
  • rules out lymphoid lineage
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14
Q

Leukocyte alkaline phosphatase assay

A
  • high in leukemoid reaction (normal inflammatory/infxn resp)
  • low in leukemia
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15
Q

B-cell CD development

A
  • DR, CD34
  • DR, CD34, CD19
  • DR, , CD10, CD19(pro B cell)
  • DR, , CD10, CD19, CD20 (pre B cell)
  • DR, , , CD19, CD20, CD 21, CD 22, SIG (Naive Bcell)
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16
Q

T cell CD development

A
  • CD 34
  • CD 34, CD 2, CD 5, CD 7
  • , CD 2, CD 5, CD 7, CD 1 (early thymocyte)
  • , CD 2, CD 5, CD 7, CD 1, CD 4, CD 8 (common tcyte)
  • Th 1: CD 3, CD 2, CD 8 (mature T cell)
  • Th 2: CD 3, CD 2, CD 4 (mature T cell)
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17
Q

MHC I, MHC II

A
  • MHC I: 6 of 200
    ~ CD 8 cytotoxic
  • MHC II: 8 of 230
    ~ CD 4 helpers
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18
Q

AML targeted therapies

A
  • CD 33
  • CD 33 Calichemicin (drug conjugate)
  • CD 33 Bi 213 (isotope conjugate)
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19
Q

Three branches of signal transduction for drug targets

A
  • Ras -> MAP (potential inhibitor target: anti-farnesylation)
  • JAK STAT (Erlotinib)
  • PI3K/PTEN
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20
Q

STI-571

A
  • Gleevec

- tyrosine kinase inhibitor for treatment in CML

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21
Q

Stimulation of P53

A
  • deletion of gene in undifferentiated HL-60
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22
Q

Stimulation of N-Ras

A
  • oncogenic activity

- constant levels in undifferentiated HL-60

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23
Q

Auer rods dare diagnostic for:

A

AML

- crystallized MPO

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24
Q

CML basics (cambronero) mutation, translocation, characteristics

A
  • full house
  • mature PMNs, metamyelocytes
  • at least one blast
  • Philadelphia chromosome (9/22), TRK expression
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25
Q

AML basics (cambronero) mutation, translocation, characteristics

A
  • AML1/ETO complexes with repressor and halt differentiation
  • 8;21
  • lots of blasts: large roundish shaped nuclei pale blue cytoplasm with salmon inclusions clear nucleoli
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26
Q

Burkitts lymphoma

A
  • 8;14 -> Ig/MYC (sludge blood)

- cell proliferation similar to CML

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27
Q

Precursor B-cell neoplasms (origin, eg) (2)

A
  • bone marrow

- b-lymphoblastic leukemia

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28
Q

Pre-germinal center neoplasm (location, eg) (2)

A
  • intrafollicular area

- mantle cell Lymphoma

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29
Q

Germinal center neoplasms (location, eg) (5)

A
  • GC
  • follicular lymphoma
  • burkitts
  • DLBCL
  • Hodgkin lymphoma
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30
Q

Post GC neoplasms (location eg) (5)

A
  • peri follicular area
  • marginal zone and malt lymphomas
  • lymphoplasmacytic lymphoma
  • CLL/SLL, DLBCL
  • plasma cell myeloma
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31
Q

Cellular Origin of most lymphoid neoplasms

A
  • B cells, usually wide spread at time of diagnosis -> systemic trt
  • rest are T cells
  • NK cell, histiocytic origin rare
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33
Q

B cell associated markers (9)

A
  • CD 10, CD 19, CD 20, CD 21, CD 22, CD 23, CD79a, pax-5, oct-2
  • precursors TdT positive
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34
Q

Myeloid associated markers (6)

A
  • CD 117, CD 13, CD 14, CD15, CD 11b, CD 33
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35
Q

NK associated markers (3)

A
  • CD 16, CD 56, CD 57
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36
Q

BALL characteristics

A
  • 20% blast count
  • ly primary in kids
  • typically exhibit tcytopenia, anemia, neutropenia
  • lymphadenopathy, hepatomegaly, splenomegaly
  • bone pain in kids is a clinical clue (esp rib)
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37
Q

BALL diagnostic info (morphology, enzyme, markers)

A
  • BM aspirate shows sheets of blasts
  • MPO (-)
  • TdT (+), HLA-DR, CD19, CD79 and most are CD10(+)
  • 9;22 more common in adult form
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38
Q

4;11 BALL

A

Usually CD10 (-)

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39
Q

Factors of BALL with a good prognosis (3)

A
  • hyperdiploid
  • 12;21 tlcn, TEL-AML1
  • children (2-10)
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40
Q

BALL with a bad prognosis

A
  • all the translocations that aren’t 12;21
  • 9;22 tlcn
  • 11q23
  • 1;19
  • Hypodiploid
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41
Q

TLL characteristics

A
  • most are precursor T cell type
  • typically involves mediastinal tumor
  • cells morphologically similar to B lymphoblasts
  • more common in adolescent males
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42
Q

TLL diagnostic markers

A
  • CD 1,2,3,4,5,6,7,8 (+), TdT may be positive
  • CD 3 most often (+)
  • typically arises from txn factor dysregulation
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43
Q

CLL/SLL characteristics

A
  • B cell lymphoma
  • 90% of chronic lymphoid leukemias
  • more common in older males
  • autoimmune hemolytic anemia, infxns, splenomegaly, hepatomegaly, lymphadenopathy
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44
Q

CLL/SLL diagnostic (not mantle)

A
  • flow cytometry
  • most commonly CD 19, 20, 22, IgM/D
  • fewer light chains and CD20
  • CD5 and CD23 are almost always present
  • cyclin D1 is negative
  • FISH may reveal trisomy 12 (bad)
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45
Q

CLL/SLL prognosis

A
  • trisomy 12 and 11q deletions have poorer prognosis

- not considered to be curable but usually indolent

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46
Q

CLL/SLL prognosis

A
  • trisomy 12 and q11 deletion is bad
  • rapid doubling time is bad
  • can become richters syndrome (high grade lymphoma) in ~ 4%
47
Q

Lymphoplasmacytic lymphoma (waldenstrom macroglobinemia) characteristics

A
  • B-cell plasmacytoid involving blond marrow, lymphnodes and spleen
  • lack CD5 co-expression
  • hyperviscosity and cryoglobinemia common
48
Q

Lymphoplasmacytic lymphoma (waldenstrom macroglobinemia) diagnostic

A
  • IgM serum paraprotein and potential hyperviscosity symptoms
  • neuropathies and skin/GI symptoms can also occur
  • Rouleaux formation can occur
  • t 9;14 and PAX-5 rearrangements
49
Q

Splenic/marginal zone lymphoma characteristics

A
  • small lymphocytes which surround and replace white pulp
  • rarely express CD5
  • common in older PTs
50
Q

Splenic/marginal zone lymphoma diagnostic

A
  • typically lack CD5, CD10, CD23, and CD43

- typically CD20, CD19 (+)

51
Q

Splenic/marginal zone lymphoma prognosis

A
  • typically indolent

- response to chemo is typically poor, but splenectomy improves prognosis long term

52
Q

Hairy cell leukemia characteristics and diagnostics

A
  • predominantly middle aged white men
  • presents with pancytopenia and splenomegaly
  • in peripheral blood, marrow and splenic red pulp (Trap + trapped in red pulp)
  • strongly expresses CD103, CD22, CD11c and CD25
53
Q

Hairy cell leukemia treatment

A
  • highly sensitive to trt with purine nucleoside 2-chlorodeoxyadenosine
  • long lasting remission
54
Q

Follicular lymphoma characteristics

A
  • most common type of non-hodgkins lymphoma in USA and Western Europe
  • rarely in younger people (<20)
  • usually has modular morphology due to follicular organization
55
Q

Follicular lymphoma diagnostic

A
  • positive for CD10,19 and 20
  • CD5 is generally not expressed
  • BCL-2 over expression
60
Q

T cell associated markers

A
  • CD 1-8

- precursor T cells will be TdT positive

61
Q

Follicular lymphoma presentation prognosis

A
  • Usually presents as generalized lymphadenopathy
  • incurable waxing and waning
  • aggressive transformation occurs in over 1/4
62
Q

Diffuse large B-cell lymphoma characteristics

A
  • rarely seen in kids; associated with NHLy
  • diffuse sheets of large lymphocytes
  • CD19, 20 and PAX-5
  • may have CD 10
  • over 1/4 contain t 14;18
63
Q

Diffuse large B-cell lymphoma presentation, prognosis

A
  • generally presents with rapidly enlarging symptomatic mass at a nodal or extra nodal site
  • complete remission in about 70%
64
Q

Mantle cell neoplasms

A
  • monomorphous small-medium angular end nuclei lcytes
  • over expression of Cyclin D1
  • generally in nodes
  • t11;14 with FISH
  • it’s aggressive with median survival of 3-5 years
65
Q

Burkitts lymphoma characteristics

A
  • aggressive B-cell type, basophilic cytoplasm with numerous mitotic figures
  • MYC/Ig
  • Epstein Barr is a common finding
  • large nucleus with vacuoles
66
Q

Types of burkitts lymphoma (3)

A
  • endemic (jaws, higher incidence of EBV)
  • sporadic (abdominal masses)
  • immune-deficiency BL
67
Q

Burkitts lymphoma diagnostics and trt

A
  • MYC at 8q24
  • always CD10 positive, usually CD19, CD20, CD22
  • highly aggressive but treatable: 90% complete remission
  • 2 years w/out relapse = cured
68
Q

Extranodal marginal zone B cell lymphoma of MALT appearance and associated conditions

A
  • hetogenous mix of small Bcells, lcytes and plasmas
  • typically infiltrates epithelium
  • associated with H. Pylori, Sjorgrens syndrome and hashimotos
69
Q

MALT lymphoma

A
  • most common in stomach
  • CD19,20 and 79a (+)
  • CD5, 10 and 23 (-)
  • trisomy 13 in over 1/2
  • t11;18 in over 1/4 (resistant to H. Pylori irradiation)
70
Q

Plasma cell neoplasms Characteristic

A
  • clonal expansion of terminally differentiated plasma cell
  • “M component” Secretion (single homogenous Ig product: Ig kappa protein)
  • M component can be seen in both malignant and pre malignant disorders
71
Q

Plasma cell myeloma characteristics and presentation

A
  • Bone marrow multifocal plasma cell neoplasm
  • Bone pain, osteolytic lesions, fractures, hypercalcemia, anemia
  • urine bence-jones light chain dimers
  • may be indolent or aggressive
72
Q

Plasma cell myeloma diagnostic

A
  • more common in African Americans
  • common overall
  • increased plasma cells in marrow and soft tissue, bence-jones proteins, bone lesions, and decreased serum Ig
73
Q

MGUS

A
  • pre malignant state for many cancers (myeloma, waldenstrom, et al)
  • serum M component is < 3 Mg/dl and lack BJPs
  • about 1/4 progress to malignancy
74
Q

Multiple myeloma prognosis

A
  • typically incurable: MST (mean survival time) ~ 3-4 years

- factors include amt of M comp, BJPs, serum Ca, B2 microglobulin and plasma replacement

75
Q

Lymphomas associated with HIV (5)

A
  • Burketts lymphoma
  • Diffuse large B cell lymphoma
  • Primary effusion lymphoma caused by HHV8
  • Plasma blastic lymphoma associated with EBV
  • Hodgkins
76
Q

TPL characteristics and trt/prognosis

A
  • aggressive, proliferation of prolymphocytes with mature post thymic Tcells phenotype
  • median survival is less than a year
  • may respond to anti CD-52
77
Q

T cell large granular lymphocytic leukemia

A
  • persistent (6mo) elevation in grans
  • 2,000-20,000 microliters w/out clearly ID cause
  • documentation of TCR rearrangement is req to diagnose
78
Q

Mycosis fungoides characteristics

A
  • Clusters of infiltrating mature T cells into the skin

- over the course of years

79
Q

Mycosis Fungoides

A
  • CD 2345 (+) CD8(-)

- lacks CD7 (this is also seen in benign cutaneous lesions)

80
Q

Sezary syndrome

A
  • Generalized mature T-cell lymphoma
  • variant of MYC. fung. But much more aggressive
  • presents with erythroderma, lymphadenopathy, neoplastic tlcytes in blood
81
Q

2 main types of non-hodgkins lymphoma in US

A
  • Large diffuse Bcell lymphoma
  • follicular lymphoma
  • over 1/2
82
Q

Hodgkin’s lymphoma overview

A
  • typically cervical lymphnode origin
  • typically in young adults
  • reed-steinberg cells
  • neoplastic cells typically rosetted by t-lcytes
  • now mostly curable
83
Q

Classical Hodgkin’s lymphoma

A
  • modular sclerosis
  • mixed cellularity
  • lymphocyte depleted
  • lymphocyte rich
84
Q

Ann Arbor staging of HL

A
  1. Single node/extra lymphatic site
  2. Either two nodes or involvement with extra lymphatic site
  3. Nodes on both sides of diaphragm, may include spleen or extra lymph site
  4. Multi/disseminated foci
85
Q

H vs. NHL

A
  • lymphnodes:H-single (cervical, medst, pariaortic) NH- multiple
  • spread:H-orderly, NH-non contiguous spread
  • waldeyers ring:H-rarely involved, NH-commonly involved
  • extra nodal evolvement: H-rare, NH-common
86
Q

CML characteristics

A
  • bcr/abl, commonly t9;22 (Philly)
  • neutrophilic leukocytosis
  • indolent phase followed by aggressive phases: accelerated and blast phases
87
Q

CML clinical phases

A
  • high WBC and splenomegaly are common presentations
    Chronic: peripheral blood shows marked granulocytosis in different stages
    ~ blasts account for less than 2%

Accelerated: blast count increases 10-20%, tcytopenia, tcytosis, splenomegaly, clonal evolution

Blast phase: blast > 20%/nucleated cells in marrow And/Or extra medullary proliferation of blasts
~ blast aggregates in marrow
~ about 25 % of CML in blast phase blasts are lymphocytic

88
Q

CML diagnosis and trt

A
  • almost all cases have bcr/abl; FISH/PCR
  • STI571 (Gleevec) TRK inhibitor
    ~ significant impact on prognosis
89
Q

Polycythemia Vera characteristics

A
  • myloproliferative from clonal hematopoietic expansion
  • excessive proliferation
  • biphasic: initial proliferative (increased red cell mass), post-polycythemic (anemias, cytopenias marrow fibrosis, extra medullary hematopoiesis and hypersplenism)
90
Q

Major criteria for diagnosis of PV

A
  • Hb > 18.5 (m), 16.5 > 16.5 (f)

- JAK-2 mutation (V617F on 14 or JAK2 on 12)

91
Q

Minor criteria

A
  • BM biopsy -> hypercellularity for age with trilineage growth
  • serum EPO below normal
  • endogenous erythroid colony formation in vitro
92
Q

PV prognosis

A
  • w/out trt only a few months; w/ trt > 10 years
  • mortality from thrombosis/hemorrhage
  • 20% progress to AML or myleodysplasia
93
Q

Primary myelofibrosis

A
  • proliferation of mainly the megakaryocytes and granulocytes
  • stepwise progression:
    ~ prefibrotic: hypercellular in marrow
    ~ fibrotic: marked reticulin/collagen fibrosis and osteosclerosis
94
Q

PMF clinical and prognosis

A
  • philadelphia (-)
  • teardrop shaped RBCs (fibrotic), leukoerythroblastosis, poikilocytosis
  • hepatosplenomegaly
  • morbidity: bone marrow failure, thromboembolic events, portal HTN, progression to acute leukemia
  • 3-5 year survival
95
Q

Essential thrombocytopenia

A
  • primarily megakaryocytic origin
  • thrombocytosis and increased large megakaryocytosis
  • Philly chromosome is negative
  • generally indolent interrupted by thromboembolic/hemorrhagic events
  • mean survival 10-15 years
  • progression to AML is rare
96
Q

AML with 8;21

A

About 5% of aml cases

  • younger PTs
  • 20% of blasts not required for this type of leukemia
  • good prognosis
  • CD13,19,33 (+)
  • MPO positive
97
Q

AML with 16 inversion

A
  • CBFB gene fuses to myosin smooth muscle myosin heavy chain
  • achieve higher remission rates when treated with cytarabine in consolidation phase
98
Q

APL (t15;17 variant)

A
  • RAR/PML
  • associated with DIC
  • abnormal promyelocytes predominate
  • occasional clusters of auer rods
  • strongly positive for myeloperoxidase
  • CD13, CD33
99
Q

AML treatment and diagnosis

A
  • sensitive to all trans retinoic acid

- adding an anthracyclines (doxorubicin) -> more favorable outcome

100
Q

AML 11;23 variant

A
  • infants and therapy related leukemia
101
Q

Itrogenic AML

A
  • presents as myleodysplasia with evidence of bone marrow failure
  • heterogenous morphology
  • 5 and 7 deletions commonly involved
102
Q

Myleodysplasia syndrome

A
  • Dysplasia and ineffective hematopoiesis in one or more of the major myeloid lines
  • myeloblasts in marrow are less than 20%
  • often progresses to AML
  • nutritional deficiencies, toxic exposure and cytotoxic therapy
103
Q

MDS prognosis (high and low risk)

A
  • low risk: refractory anemia, refractory anemia with ring sideroblasts
  • high risk: refractory anemia with excess blasts, refractory cytopenia with multi lineage dysplasia, with or without ring sideroblasts
104
Q

5q MDS

A
  • primarily in middle aged/older women
  • most common symptoms related to severe refractory anemia
  • only 5q deletion between 31-33
  • good prognosis
105
Q

Eosinophilia in lymphoma

A
  • can occur in hodgkins
106
Q

t9;22 and t12;21 as prognostic factors

A
  • t9;22: Philadelphia chromosome, bad prognosis for BALL

- t21;21: BALL finding more common in kids, good prognostic factor

107
Q

Bone pain in kids (esp. Ribs)

A
  • B-ALL
  • hepatosplenomegaly
  • tcytopenia, anemia, neutropenia
108
Q

CD 11c, 22, 25 and 103

A

Hairy cell leukemia

Treat with2-chlorodeoxyadenosine

109
Q

CD 5, 10, 23, 43

A

Marginal zone/splenic B cell lymphoma

110
Q

Tdt+, CD 10, 19, 79a

A

BALL

-4;11 variant CD 10 (-)

111
Q

Erythroderma as symptom

A

Murcosis fungoides

112
Q

CD 79a

A
  • immature B cell marker

- B-ALL

113
Q

B symptoms

A
  • From reed-steinberg
  • fever, chills, night sweats, weight loss
  • can often include fibrosis
114
Q

Therapy initiated AML prognosis

A
  • very poor
115
Q

Don’t need 20% blasts for (2)

A
  • AML variants
  • Inv 16
  • 8;21
116
Q

An acute leukemia not requiring 20% blasts

A

AML 8;21 variant

- ETO

117
Q

8;14, s-phase blasts

A

Burkitt’s lymphoma

118
Q

Ringed sideroblasts in MDS

A
  • good prognosis

Heme (7 decks)

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