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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
CML basics (cambronero) mutation, translocation, characteristics
- full house - mature PMNs, metamyelocytes - at least one blast - Philadelphia chromosome (9/22), TRK expression
25
AML basics (cambronero) mutation, translocation, characteristics
- 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
26
Burkitts lymphoma
- 8;14 -> Ig/MYC (sludge blood) | - cell proliferation similar to CML
27
Precursor B-cell neoplasms (origin, eg) (2)
- bone marrow | - b-lymphoblastic leukemia
28
Pre-germinal center neoplasm (location, eg) (2)
- intrafollicular area | - mantle cell Lymphoma
29
Germinal center neoplasms (location, eg) (5)
- GC - follicular lymphoma - burkitts - DLBCL - Hodgkin lymphoma
30
Post GC neoplasms (location eg) (5)
- peri follicular area - marginal zone and malt lymphomas - lymphoplasmacytic lymphoma - CLL/SLL, DLBCL - plasma cell myeloma
31
Cellular Origin of most lymphoid neoplasms
- B cells, usually wide spread at time of diagnosis -> systemic trt - rest are T cells - NK cell, histiocytic origin rare
33
B cell associated markers (9)
- CD 10, CD 19, CD 20, CD 21, CD 22, CD 23, CD79a, pax-5, oct-2 - precursors TdT positive
34
Myeloid associated markers (6)
- CD 117, CD 13, CD 14, CD15, CD 11b, CD 33
35
NK associated markers (3)
- CD 16, CD 56, CD 57
36
BALL characteristics
- 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)
37
BALL diagnostic info (morphology, enzyme, markers)
- BM aspirate shows sheets of blasts - MPO (-) - TdT (+), HLA-DR, CD19, CD79 and most are CD10(+) - 9;22 more common in adult form
38
4;11 BALL
Usually CD10 (-)
39
Factors of BALL with a good prognosis (3)
- hyperdiploid - 12;21 tlcn, TEL-AML1 - children (2-10)
40
BALL with a bad prognosis
- all the translocations that aren't 12;21 - 9;22 tlcn - 11q23 - 1;19 - Hypodiploid
41
TLL characteristics
- most are precursor T cell type - typically involves mediastinal tumor - cells morphologically similar to B lymphoblasts - more common in adolescent males
42
TLL diagnostic markers
- CD 1,2,3,4,5,6,7,8 (+), TdT may be positive - CD 3 most often (+) - typically arises from txn factor dysregulation
43
CLL/SLL characteristics
- B cell lymphoma - 90% of chronic lymphoid leukemias - more common in older males - autoimmune hemolytic anemia, infxns, splenomegaly, hepatomegaly, lymphadenopathy
44
CLL/SLL diagnostic (not mantle)
- 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)
45
CLL/SLL prognosis
- trisomy 12 and 11q deletions have poorer prognosis | - not considered to be curable but usually indolent
46
CLL/SLL prognosis
- trisomy 12 and q11 deletion is bad - rapid doubling time is bad - can become richters syndrome (high grade lymphoma) in ~ 4%
47
Lymphoplasmacytic lymphoma (waldenstrom macroglobinemia) characteristics
- B-cell plasmacytoid involving blond marrow, lymphnodes and spleen - lack CD5 co-expression - hyperviscosity and cryoglobinemia common
48
Lymphoplasmacytic lymphoma (waldenstrom macroglobinemia) diagnostic
- 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
Splenic/marginal zone lymphoma characteristics
- small lymphocytes which surround and replace white pulp - rarely express CD5 - common in older PTs
50
Splenic/marginal zone lymphoma diagnostic
- typically lack CD5, CD10, CD23, and CD43 | - typically CD20, CD19 (+)
51
Splenic/marginal zone lymphoma prognosis
- typically indolent | - response to chemo is typically poor, but splenectomy improves prognosis long term
52
Hairy cell leukemia characteristics and diagnostics
- 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
Hairy cell leukemia treatment
- highly sensitive to trt with purine nucleoside 2-chlorodeoxyadenosine - long lasting remission
54
Follicular lymphoma characteristics
- 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
Follicular lymphoma diagnostic
- positive for CD10,19 and 20 - CD5 is generally not expressed - BCL-2 over expression
60
T cell associated markers
- CD 1-8 | - precursor T cells will be TdT positive
61
Follicular lymphoma presentation prognosis
- Usually presents as generalized lymphadenopathy - incurable waxing and waning - aggressive transformation occurs in over 1/4
62
Diffuse large B-cell lymphoma characteristics
- 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
Diffuse large B-cell lymphoma presentation, prognosis
- generally presents with rapidly enlarging symptomatic mass at a nodal or extra nodal site - complete remission in about 70%
64
Mantle cell neoplasms
- 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
Burkitts lymphoma characteristics
- aggressive B-cell type, basophilic cytoplasm with numerous mitotic figures - MYC/Ig - Epstein Barr is a common finding - large nucleus with vacuoles
66
Types of burkitts lymphoma (3)
- endemic (jaws, higher incidence of EBV) - sporadic (abdominal masses) - immune-deficiency BL
67
Burkitts lymphoma diagnostics and trt
- MYC at 8q24 - always CD10 positive, usually CD19, CD20, CD22 - highly aggressive but treatable: 90% complete remission - 2 years w/out relapse = cured
68
Extranodal marginal zone B cell lymphoma of MALT appearance and associated conditions
- hetogenous mix of small Bcells, lcytes and plasmas - typically infiltrates epithelium - associated with H. Pylori, Sjorgrens syndrome and hashimotos
69
MALT lymphoma
- 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
Plasma cell neoplasms Characteristic
- 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
Plasma cell myeloma characteristics and presentation
- 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
Plasma cell myeloma diagnostic
- 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
MGUS
- 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
Multiple myeloma prognosis
- typically incurable: MST (mean survival time) ~ 3-4 years | - factors include amt of M comp, BJPs, serum Ca, B2 microglobulin and plasma replacement
75
Lymphomas associated with HIV (5)
- Burketts lymphoma - Diffuse large B cell lymphoma - Primary effusion lymphoma caused by HHV8 - Plasma blastic lymphoma associated with EBV - Hodgkins
76
TPL characteristics and trt/prognosis
- aggressive, proliferation of prolymphocytes with mature post thymic Tcells phenotype - median survival is less than a year - may respond to anti CD-52
77
T cell large granular lymphocytic leukemia
- persistent (6mo) elevation in grans - 2,000-20,000 microliters w/out clearly ID cause - documentation of TCR rearrangement is req to diagnose
78
Mycosis fungoides characteristics
- Clusters of infiltrating mature T cells into the skin | - over the course of years
79
Mycosis Fungoides
- CD 2345 (+) CD8(-) | - lacks CD7 (this is also seen in benign cutaneous lesions)
80
Sezary syndrome
- Generalized mature T-cell lymphoma - variant of MYC. fung. But much more aggressive - presents with erythroderma, lymphadenopathy, neoplastic tlcytes in blood
81
2 main types of non-hodgkins lymphoma in US
- Large diffuse Bcell lymphoma - follicular lymphoma - over 1/2
82
Hodgkin's lymphoma overview
- typically cervical lymphnode origin - typically in young adults - reed-steinberg cells - neoplastic cells typically rosetted by t-lcytes - now mostly curable
83
Classical Hodgkin's lymphoma
- modular sclerosis - mixed cellularity - lymphocyte depleted - lymphocyte rich
84
Ann Arbor staging of HL
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
H vs. NHL
- 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
CML characteristics
- bcr/abl, commonly t9;22 (Philly) - neutrophilic leukocytosis - indolent phase followed by aggressive phases: accelerated and blast phases
87
CML clinical phases
- 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
CML diagnosis and trt
- almost all cases have bcr/abl; FISH/PCR - STI571 (Gleevec) TRK inhibitor ~ significant impact on prognosis
89
Polycythemia Vera characteristics
- 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
Major criteria for diagnosis of PV
- Hb > 18.5 (m), 16.5 > 16.5 (f) | - JAK-2 mutation (V617F on 14 or JAK2 on 12)
91
Minor criteria
- BM biopsy -> hypercellularity for age with trilineage growth - serum EPO below normal - endogenous erythroid colony formation in vitro
92
PV prognosis
- w/out trt only a few months; w/ trt > 10 years - mortality from thrombosis/hemorrhage - 20% progress to AML or myleodysplasia
93
Primary myelofibrosis
- proliferation of mainly the megakaryocytes and granulocytes - stepwise progression: ~ prefibrotic: hypercellular in marrow ~ fibrotic: marked reticulin/collagen fibrosis and osteosclerosis
94
PMF clinical and prognosis
- 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
Essential thrombocytopenia
- 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
AML with 8;21
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
AML with 16 inversion
- CBFB gene fuses to myosin smooth muscle myosin heavy chain - achieve higher remission rates when treated with cytarabine in consolidation phase
98
APL (t15;17 variant)
- RAR/PML - associated with DIC - abnormal promyelocytes predominate - occasional clusters of auer rods - strongly positive for myeloperoxidase - CD13, CD33
99
AML treatment and diagnosis
- sensitive to all trans retinoic acid | - adding an anthracyclines (doxorubicin) -> more favorable outcome
100
AML 11;23 variant
- infants and therapy related leukemia
101
Itrogenic AML
- presents as myleodysplasia with evidence of bone marrow failure - heterogenous morphology - 5 and 7 deletions commonly involved
102
Myleodysplasia syndrome
- 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
MDS prognosis (high and low risk)
- 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
5q MDS
- primarily in middle aged/older women - most common symptoms related to severe refractory anemia - only 5q deletion between 31-33 - good prognosis
105
Eosinophilia in lymphoma
- can occur in hodgkins
106
t9;22 and t12;21 as prognostic factors
- t9;22: Philadelphia chromosome, bad prognosis for BALL | - t21;21: BALL finding more common in kids, good prognostic factor
107
Bone pain in kids (esp. Ribs)
- B-ALL - hepatosplenomegaly - tcytopenia, anemia, neutropenia
108
CD 11c, 22, 25 and 103
Hairy cell leukemia | Treat with2-chlorodeoxyadenosine
109
CD 5, 10, 23, 43
Marginal zone/splenic B cell lymphoma
110
Tdt+, CD 10, 19, 79a
BALL | -4;11 variant CD 10 (-)
111
Erythroderma as symptom
Murcosis fungoides
112
CD 79a
- immature B cell marker | - B-ALL
113
B symptoms
- From reed-steinberg - fever, chills, night sweats, weight loss - can often include fibrosis
114
Therapy initiated AML prognosis
- very poor
115
Don't need 20% blasts for (2)
- AML variants - Inv 16 - 8;21
116
An acute leukemia not requiring 20% blasts
AML 8;21 variant | - ETO
117
8;14, s-phase blasts
Burkitt's lymphoma
118
Ringed sideroblasts in MDS
- good prognosis

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