Under representation of bcr1 subtype of PML-RAR
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Apml

Under representation of bcr1 subtype of PML-RARα fusion gene in APML in Indian patientsSudha Sazawal, Syed k Hasan, Bijender Kumar, Pankhi Dutta, Rajat Kumar, Lalit Kumar*, VP Choudhry, Renu Saxena Departments of Hematology and *Medical Oncology,All India Institute of Medical Sciences, New Delhi- 29


Apml

APML

AML subtype: good response to ATRA

Problems/ dilemma associated with APML:

  • Diagnosis (morphologic M2/M4 may be confused)

  • Response to ATRA: variable.

percent


Pathogenesis of apml

Pathogenesis of APML

Molecular defects

  • PML-RARα- t(15;17): good prognosis (99%)

  • (NPM) -t(5;17) – 5q35 : good prognosis

  • (PLZF) -t(11;17) – 11q23

  • (NUMA) -t(11;17) – 11q13

Bad prognosis


Techniques to detect t 15 17 pml rar

10

-8

Techniques to detect t(15;17)/ PML-RARα


Apml

RARa

PML

bcr2

bcr1

bcr

bcr3

3

4

5

6

7

2

3

4

3’

3’

5’

5’

A = Normal PML and RARa

3

4

5

6

3

4

3’

5’

B = 3’ PML breakpoint (L)

3

3

4

3’

5’

C = 5’ PML breakpoint (S)

Isoforms of APML

  • Ambiguity exists regarding the Potential independent prognostic implications of these isoforms

  • bcr 1: (Long isoform) good response to ATRA

  • bcr 3: (short isoform) poor response to ATRA


Apml

AIMS

  • Evaluation of role of PML-RARα in diagnosis of APML

  • Determination of the occurrence of breakpoint regions/ isoforms in APML in our population

  • Correlation with response to ATRA


Material

Material

Subjects: AML patients

  • Inclusion criteria

    • Increased blasts/promyelocytes

    • MPO, SB, NSE/ NASDC positive

    • No prior chemotherapy

  • Exclusion criteria

    • Pts. received prior chemotherapy

    • MDS

    • Cytochemistry revealed MPO -ve, SB -ve

      Controls: ALL patients


Apml

Molecular studies

  • RT-PCR:

    • RNA Extraction

    • Reverse transcription

    • Integrity assessed by β2 microglobulin

    • Well documented primers used (Grimwade et al 1996)

  • RQ/RT-PCR: for detection of PML-RARα isoforms (Cassinat et al 2000)

    • bcr3

    • bcr1


Apml management

APML Management

  • Induction

    • ATRA – 45 mg/m2/ day (max. 90 days)

    • Inj Daunorubicin – 60mg/m2 (day 3 onwards)

  • Consolidation – 3 cycles

    • Inj Daunorubicin – 60mg/m2

  • Maintenance – 2 years

    • ATRA – 45 mg/m2/ day x 15d (every 3 months)

    • 6MP – 60mg/m2/ day

    • MTX – 20mg/m2/ weekly


Apml

AML M2

AML M3

AML M4

AML M5

AML M6


2 microglobulin of cdna

RESULTS

β2 microglobulin of cDNA

Marker

1

2

3

4

5

6

7

8

135 bp


T 15 17 pml rar

RESULTS

t(15;17)/PML-RARα

PJD2A1

P1

P2

P3

P4

Marker

-ve Ctrl

355 bp


Apml

RESULTSPresence of PML-RARα in AML Subtypes

Number of cases : 54

percent


Apml

RESULTS

Frequency of PML-RARα Isoforms

bcr1 vs bcr3 (p=0.03)


Distribution of pml rar isoforms

Distribution of PML-RAR Isoforms

percent

(p=0.004)


Pml rar isoforms and age

PML-RAR Isoforms and Age


Apml

PML-RARα Isoforms and

median TLC

Gallagher et al Blood 1997,90:1656-63

Gonzalez et al BJH 2001,114:99-03


Apml

RESULTS

PCR results of PML-RARα fusion transcript


Conclusion

Conclusion

  • Detection of PML-RARa by RT-PCR is essential in diagnosis of AML M3 .

  • BCR3 Isoform is more common than BCR1

  • Median WBC at presentation in Indian APMLis much higher than that in the West.

  • No correlation was found between WBC and Isoforms of PML-RARA


Conclusion contd

Conclusion (Contd..)

  • No conclusive comment can be made regarding relation of bcr isoform and treatment response in this study due to small number of cases.

  • However, poorer response in India Vs West may be due to high WBC or bcr 3


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