AM McCaig

B Yadav

BC Grabiner

BW Miller

DA Fruman

DC Koboldt

DL Williams

EAR Sison

GL Uy

H Edgren

H Geng

HLM Koskela

J Hoellenriegel

JA Burger

JR Brown

K Kok

LCJ van den Berk

M Müschen

M Niedermeier

MA Whitehead

MB Meads

N Wagle

P Cingolani

RR Furman

SA Forbes

SA Mehta

SP Hunger

T Burmeister

T Nagasawa

T Pemovska

U Fischer

VT Bicocca

PubMed

S Eldfors

H Kuusanmäki

M Kontro

M M Majumder

A Parsons

O Kallioniemi

K Wennerberg

N Gökbuget

K Porkka

C A Heckman

Crossref

Leukemia

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

Eldfors, S.

Kuusanmäki, H.

Kontro, M.

Majumder, M. M.

Parsons, Alun

Edgren, H.

Pemovska, T.

Kallioniemi, O.

Wennerberg, K.

Gökbuget, N.

Burmeister, T.

Porkka, K.

Heckman, C. A.

Helsingin yliopiston digitaalinen arkisto

TCF3-PBX1 (E2A-PBX1) is a recurrent gene fusion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), which is caused by the translocation t(1;19)(q23;p13). TCF3-PBX1 BCP-ALL patients typically benefit from chemotherapy; however, many relapse and subsequently develop resistant disease with few effective treatment options. Mechanisms driving disease progression and therapy resistance have not been studied in TCF3-PBX1 BCP-ALL. Here, we aimed to identify novel treatment options for TCF3-PBX1 BCP-ALL by profiling leukemia cells from a relapsed patient, and determine molecular mechanisms underlying disease pathogenesis and progression. By drug-sensitivity testing of leukemic blasts from the index patient, control samples and TCF3-PBX1 positive and negative BCP-ALL cell lines, we identified the phosphatidylinositide 3-kinase delta (p110δ) inhibitor idelalisib as an effective treatment for TCF3-PBX1 BCP-ALL. This was further supported by evidence showing TCF3-PBX1 directly regulates expression of PIK3CD, the gene encoding p110δ. Other somatic mutations to TP53 and MTOR, as well as aberrant expression of CXCR4, may influence additional drug sensitivities specific to the index patient and accompanied progression of the disease. Our results suggest that idelalisib is a promising treatment option for patients with TCF3-PBX1 BCP-ALL, whereas other drugs could be useful depending on the genetic context of individual patients

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

Abstract

Similar works

Full text

Available Versions

Crossref

Helsingin yliopiston digitaalinen arkisto

Swepub