Rebecca L King Gerald Wertheim Michele E Paessler The Childrens Hospital of Philadelphia Perelman School of Medicine at the University of Pennsylvania Philadelphia PA Clinical History 13 year old boy ID: 648716
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Case 274T lymphoblastic leukemia with t(5;14)(q35;q32) and lineage switch to acute myeloid leukemia
Rebecca L. King, Gerald Wertheim, Michele E. PaesslerThe Children’s Hospital of PhiladelphiaPerelman School of Medicine at the University of PennsylvaniaPhiladelphia, PASlide2
Clinical History13 year old boy82% Blasts
300214
4.2Slide3
Bone Marrow : April 2009Slide4
Flow Cytometry: April 2009
CD7+/CD4+
CD14-/CD33-
CD5+/CD2-
cCD3+/TdT+
MPO-Slide5
del(9)(p21)
46,XY,t(5;14)(q35;q32),del(9)(p21.3),del(13)(q14.11q21.1)[7
].
ish
t(5;14)(IGH+;IGH-
), del(9)(p16-)
/46,idem,del(7)(p1?3p?21)[6].
/45,idem,dic(7;8
)(p1?3;p11.2),del(10)(q22)[6
].
ish
dic
(7;8)(7ptel-,7cen+,D7S486+,8cen+,MYC
+)Slide6
DiagnosisT lymphoblastic leukemiat(5;14)(q35;q32)Del 9pSlide7
Clinical HistoryDay 30 of DI: Blasts seen on peripheral smear.
5.99.143
15% blastsSlide8
Bone Marrow: 6 months after Dx
MPOSlide9
Flow Cytometry: October 2009
CD14-/CD33+
cCD3/TdT-
CD15
+
MPO+Slide10
MPO
MPO
CD3
CD3
April
2009
October
2009Slide11
Diagnosis?Therapy-related AMLorLineage switch from T-ALL to AMLSlide12
der(15)t(11;15)
del(7p)
der(4)
del(9)(p21)
1. Cryptic
t(5;14) detected by FISH with IGH
probe
2. Del 9p
67,XY,+Y,der(4)del(4)(q13.1)inv dup(4)(p12pter),del(7)(p11.2p14.1),+8,-9,del(9)(p21.3),-10,-11,-14,-15,der(15) t(11;15)(q13.1;q26),+19,+22[9].ish
der
(15)t(11;15)(MLL+,PML+)
nuc ish 11q23(MLLx3)[89/100]
nuc ish 15q22(PMLx2),17q21.1(RARAx3)[94/100]
nuc ish 9p21(p16x1),9cen(CEP9x2)[90/100]Slide13
FISH: TLX3-BCL11b t(5;14)(q35;q32) present in 84% of nuclei Image courtesy of Rhett Ketterling, MDSlide14
Final DiagnosisT lymphoblastic leukemia with t(5;14)(q35;q32) and lineage switch to acute myeloid leukemia.Slide15
TLX3-BCL11b t(5;14)(q35;q32)25% of pediatric T-ALL5-10% adult T-ALLSingle reported case of myeloid leukemiaSlide16
Coincidence or biological relationship?Slide17
TLX3Homeobox protein related to TLX1Repressive activity on transcription during embryonic developmentDadi et al. Cancer Cell, 2012. TLX1 and TLX3 suppress TCRα rearrangement via ETS1 accounting for the block in T-cell maturation seen in these T-ALLs.
Knockdown of TLX1/3 leads to apoptosis, TCRα rearrangement and cell maturationSlide18
BCL11bSu et al. Blood, 2006. Significance of this gene thought to lie in downstream T-cell-specific cis-activating elements juxtaposed to TLX3 (leads to TLX3 upregulation)Ikawa et al. Science, 2010.
BCL11b is a key checkpoint protein in T-cell development
T/NK/
Myeloid
T cell
Multipotent
HSC
T/B/
NK/
Myeloid
Eryth
/Meg
B-cell
BCL11bSlide19
Therapeutic ImplicationsMixed lineage acute leukemias are difficult to treat and have poor overall survivalAim therapy at myeloid or T component?Potential for targeted therapy aimed at suppressing TLX3 to overcome the differentiation “block”Slide20
Patient Follow-UpSwitched from T-ALL to AML therapyDid not achieve second remissionDied 2 months following AML diagnosisSlide21
AcknowledgementsCHOPGerald WertheimMichele PaesslerJackie BiegelPennDale Frank
Mayo ClinicRhett Ketterling