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1

Transcription factors regulating early B-cell development

1. IKZF1 (IKAROS)
--stem cell to lymphoid precursor
2. PAX5
--Pre-B cell I to Pre-B cell II

2

Early Precursor cell markers

CD34 and TdT

3

Common ALL markers

CD19
CD10

4

Pre-B markers

Cyto
microCD20

5

ALL can also express myeloid markers!!!

CD13
CD33
little clinical significance

6

Clinical Presentation

--75% of cases in kids under 6
--80% cure rate in kids
--50% cure rate in adults

7

10 current subtypes of B-cell and T-cell ALL

ALL w/ recurrent genetic abnormalities
--9 B-cell subtypes: ALL REQUIRE 25% MARROW BLASTS FOR DIAGNOSIS!!!
--B-ALL not otherwise specified
--T-ALL

8

9 B-cell subtypes
(**all require 25% marrow blasts for diagnosis)

t(9;22)(q34;q11.2); BCR-ABL1

t(v;11q23); MLL rearranged

t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1)

t(5;14)(q31;q32); IL3-IgH

t(1;19)(q23;p13.3); E2A-PBX1

Hyperdiploid (>50 chromosomes) (good prognosis)

Hypodiploid (<45 chromosomes) (poor prognosis)

9

t(9:22)

BCR-ABL1
Fusion protein of part of a serine-threonine kinase (BCR) to trosine kinase

****p190 (a different size than p210 seen in CML)

Class I mutation (proliferation activator)

IKZF1 transcription factor mutated in 84% of pts...Differentiation inhibitor (CLASS II)

10

t(9:22)...Clinical Presentation

Older adults (25% of ALL cases)
kids <1 (2.4% of pediatric ALL)

11

t(9:22)...Morphology

Big agranular blasts

12

t(9:22)...Immunophenotype

CD10+
CD19+
TdT+

13

t(9:22)...Prognosis

Poor

14

t(v;11q23)

MLL rearranged
fusion of transcription regulator (histone methyl transferase) to any of several partners...promiscuous!

Inhibits differentiation (Class II mutation)

Also found in AML

FLT3 mutations in 20% of cases (Class II mutation in AML)

15

t(v;11q23)...Clinical Presentation

Most common leukemia in kids!!!

16

t(v;11q23)...Morphology

Big agranular blasts

17

t(v;11q23)...Immunophenotype

*CD10-
CD19+
TdT+

18

t(v;11q23)...Prognosis

Poor

19

t(12;21)

TEL-AML1 (ETV6-RUNX1)
--Fusion protein that acts as a dominant negative transcription factor. Inhibits differentiation (Equivalent of Class II mutation)
-- 28% show a Pax5 deletion (predicted to inhibit differentiation)...
(Not what the theory predicts!)

20

t(12;21)...Clinical Presentation

Kids
25% of pediatric B-ALL

21

t(12;21)...Morphology

Big agranular blasts

22

t(12;21)...Immunophenotype

TdT+
CD34+
CD20-

23

t(12;21)...Prognosis

Good!
90% cure rate

24

T-ALL...

--Most have translocation of oncogene to TCR promotor
--Multiple Possible Partners
(i.e.t(14q11;10q24) (TCR-alpha;HOX11))

25

T-ALL...Clinical Presentation

Kids
25% of pediatric B-ALL
Often w/ thymic mass or lymph node
spleen involvement

26

T-ALL...Morphology

Big agranular blasts

27

T-ALL...Immunophenotype

TdT+
CD3+
CD5+
can express myeloid or B-cell antigens as well

28

T-ALL...Prognosis

High Risk