Acute Leukemia

Arbini

1) What is it it?
2) Tools for Dx?
3) Lineage?
4) APML ~ AML: pathophysiology

Leukemia (Acute)
032311 - Arbini
To do: [slide 5]

AML = acute myeloid leukemia, B-ALL = b lymphoblastic leukemia, T-ALL = t lymphoblastic leukemia
PNH = paroxysmal nocturnal hemoglobiuria
IHC = immunohistochemistry

what is leukemia?
dx?
linae of aculte leukemia
patho of acute myelocytic leumia as model of myeloid leukemia

What is leukemia?
- abnormal hematopoeitic tissue initiated by a leukemic stem cell - aberrant, poorly regulated
organogenesis

What is leukemia?

 Newly formed, abnormal hematopoietic tissue initaed by leukemic stem cell -> aberrant
organogenesis
 Stem cell : precursor -> hematopoietic tissue
o Non random somatic chromosomal translocation -> target TF’s

What causes leukemia?

non-random, somatic CHROMOSOMAL TRANSLOCATIONS, esp. Transcription Factors (TFs)

What is clonality?
>>A single cell has a genetic lesion that allows it to become a neoplastic cell that can reproduce
indefinitely, giving rise to other cell which are exact copies. All cells of a leukemia are clonal: arose from
a single cell and have same charcter, genotype, and immunophenotype.
[Slide 5]
Cell Lineages:
Hematopoietic stem cells (self preserving, mitosis/2mo)

Multipotent cell (wks)

``Common myeloid precursor common lymphoid precursor

(Myeloid stem cell) (Lymphoid stem cell)

Myeloblast Lymphoblast Pro-NK cell

B cells T cells NK Cells

Erythryocytes
Platelet Neutro-. eosino-,
Monocyte basophils

Dx?
- morphologically: blood/bone marrow smears
- flow cytometry (show expansion of a cell population -> CLONALITY)
- genotypically - abnormsal karyotype (translocations, additions, deletions)
- molecularly: DNA mutatios, cell clonality

What are some morphologically undifferentied leukemias?

AML, B-ALL, T-ALL, blastic NK cell leukemia =>
these all look alike and need flow cytometry to be acurately dx'd

Flow cytometry: uses fluorescently labeled antibodies, while the cytometer detects particular colors and
wavelengths through a ystem of mirrors and detectors -> determine how many/which celsl have what
surface markers (CD’s). most common tool for dx of MYELOID / LYMPHOID LEUKEMIA.

======
AML = acute myeloid leukemia
who: young vs old (single lesion -> TF vs. complex genetic lesion), mostly sporadic
congenital d/o inc risk:
Fanconi (BRCA2)
Bloom (DNA helicase)
Down (Trisomy 21)
Kostmann (neutorphil elastase -> apoptois of myeloid precursors)
Shwachman-Diamond (ribosomal biogenes / myeloid precursors)
acquired hematologic d/o: chronic myeloproliferative, myelodysplastic neoplasmas, PNH
genetic damage: radiation, benzene

outcome: cytogenetic aberrations / abnormal karyotype – most predictive for progonsis

Morphology of AML >20% blasts

AML = >20% blasts in peripheral blood, bone marrow
(unlike lymphoblastic leukemia = any blasts in blood/bM = abnormal)
bLAST = immature undifferentiated hematolymphoid precursor
 <20% blasts = myelodysplasia, chronic myeloproliferative neoplasm
histo: Auer rods = crystalized myeloperoxidase -> w/o, use IHC / flow cytometry

Classification of AML:
 w/ recurrent genetic abnormalities
o APML (acute promyelocytic leukemia) – model of AML t(15;17)
o AML – t(8;21)
o AML w/ abnormal eosinopils inv(16)
 w/ myelodysplasia related changes (prior myeloid dysplasia)
 & MDS – tx related (chemo alkylating -> DNA damage -> inc’d risk, worse prognosis)
 NOS (50% unknown)
Causes of AML (032311_Raphael)
 Impaired differentiation, self-renewing stem cells, heterogeneity (tumors can change with time)

Origin of APML?
 Promyelocytes – only leukemia to arise from; most come from myelocytes
 University of
Minnesota

APL = Acute promyelocytic leukemia

Summary Comments
Genetics T(15;17) of PML gene and retinoid Translocation of PML gene (chr 15) and
receptor retinoid receptor (chr 17)

Who? Younger adults but occurs at any age

Presents DIC Freq presentation with disseminated
(petechiae) intravascular coagulation.

High mortality (cytokine cascade -> DIC ->

death)

Histo Aberrant monocytes w/ granules NOT blasts (rim of cytoplasm around

nucleus)

Abundant granules w/ myeloperoxidase.

(and other) enzymes released ->DIC

Dx Acute leukemia + positive Cytochemical staind for myeloidperoxidase.

myeloperxoidase stain If stains undifferenated cell: a myeloblast.
One of few cytochemical stains still used
Markers CD13. CD33 Myeloid origin
CD34 Immature: only blasts (if hematopoetic,
CD34+)
Pathogenesis? Mutated RAR transcript permanently RAR = retinoic acid receptor -> too high
represses maturation genes affinity for repressor of transcription

Thus promyelocytic cells can never mature

Treatment ATRA ATRA =All-trans-retinoic acid
Extremely high levels of Vitamin A

 T(15;17) of PML gene and retinoid receptor

 Dx – histology – aberrant promyelocytes
o Characteristic aberrant monocytes:
BLL= B lymphoblastic leukemia/lymphoma

Summary Comments
Who? Kids < 5 (75%)
Presents? Leukemia (85%) Leukemia: bone marrow involvement;
Lymphoblastic lymphoma (10%, rare) spleen, liver, gonads, CNS
Histo Blasts Undifferentiated hematopoetic cell
clusters w/ loose chromatin

Can’t distinguish -> use flow cytometry to

dx

Dx Flow cytometry B-cells: CD19+

Immature: Lamda-/Kappa-, TdT+, CD34+

Prognosis Good: t(12;21), > 49 chromsomes Cytogenetic abnromalities are crucial for
Bad: everything else prognosis: 21 is good!

Bad - (MLL t(4;11)), mixed leukemia,

lymphoma gene
T= T lymphoblastic leukemia/lymphoma

Summary Comments
Who Teens, young adults
Presents Mediastinal mass Bc tcells mature in thymus!
Dx / Markers T-cell markers: variable Only t-lymphocytes in thymus have CD1a.,
CD3- surface, + in cytoplasm
CDa1, TdT = immature t-
lymphocytes

Thymocyte stages of differentiation: Cd1a for cortical thymocytes.

Flow cytometry

`How do you read one? The A

Markers CD13. CD33 Myeloid origin

CD34 Immature: only blasts (if hematopoetic,
CD34+)
CD14 Monocytic

CD 45 LCA –rule out lymphoid origin of tumor

LC A = leukocyte common antigen (hemato-
lymphoid lineage)
Myloid markers = CD 15/17
CD 15/17 = myleoid markers CD 13/33 = myloid markers

CD 34 = immature marker

T-cells CD1-5, 7-10

B-cells CD19, 20, 22, 24
Immature b-cells Kappa/lamba negative
CD34,. TdT
TdT Enzyme in nuclus of immature b-cells