“3C-UP” A NEW ADULT PHILADELPHIA NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA SUBGROUP: NOVEL MOLECULAR MARKERS
Author(s): ,
Anna Ferrari
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy;DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
Silvia Vitali
Affiliations:
Dipartimento di Fisica e Astronomia,INFN,Bologna University,Bologna,Italy
,
Valentina Robustelli
Affiliations:
DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
Andrea Ghelli Luserna di Rorà
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Carmen Baldazzi
Affiliations:
DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
Simona Righi
Affiliations:
DIMES,Hematopathology Unit,Bologna,Italy
,
Eugenio Fonzi
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Serena De Matteis
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Martina Ghetti
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Roberta Napolitano
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Michela Tebaldi
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Samanta Salvi
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Cristina Papayannidis
Affiliations:
DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
Giovanni Marconi
Affiliations:
DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
Stefania Paolini
Affiliations:
DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
Giulia Ferrari
Affiliations:
DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
MC Fontana
Affiliations:
DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
Enrica Imbrogno
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Antonella Padella
Affiliations:
DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
Giorgia Simonetti
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Giovanni Pasquini
Affiliations:
Dipartimento di Fisica e Astronomia,INFN,Bologna University,Bologna,Italy
,
Alessandra Santoro
Affiliations:
Hematology department,A.O. Ospedali Riuniti Villa Sofia-Cervello,Palermo,Italy
,
JM Hernández-Rivas
Affiliations:
Fundación de Investigación del Cáncer,Universidad de Salamanca,Salamanca,Spain
,
Daniele Calistri
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Bioscience Laboratory,Meldola (FC),Italy
,
Gastone Castellani
Affiliations:
Dipartimento di Fisica e Astronomia,INFN,Bologna University,Bologna,Italy
,
Elena Sabattini
Affiliations:
DIMES,Hematopathology Unit,Bologna,Italy
,
Nicoletta Testoni
Affiliations:
DIMES,Ist. Di Ematologia, Bologna University,Bologna,Italy
,
Daniel Remondini
Affiliations:
Dipartimento di Fisica e Astronomia,INFN,Bologna University,Bologna,Italy
Giovanni Martinelli
Affiliations:
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.),Department of Medical Oncology,Meldola (FC),Italy
EHA Library. Ferrari A. Jun 15, 2019; 267229; PS928
Dr. Anna Ferrari
Dr. Anna Ferrari
Contributions
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Abstract

Abstract: PS928

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
The adult “triple negative” [Ph-/-/-; neg for t(9;22); t(1;19); t(4;11); 61% of adult B-ALL (Roberts KG et al., JCO. 2017)] B-ALL group is characterized by an high genetic heterogeneity and poor survival. Many very low freq subgroups have been recently distinguished in a very large international cohort of pts (Gu Z, NatGenet. 2019); identified them (also Ph-like) is challenging cause to genetic complexity, to not unique worldwide guidelines and to expensive algorithms that require multi-NGS approaches. CRLF2 is frequently altered in adult B-ALL, especially in Ph-like (50-75% of cases) and Ph- pts. Alterations that lead, in the majority of cases, to a CRLF2 overexpr.. Adult pts with CRLF2 upreg have poor outcome and novel strategies are needed to improve it.

Aims
We focused to CRLF2 overexpr. event to understand the genomic background of all Ph-/-/- ALL and subsequently clustering the Ph-/-/-, in order to assess biomarkers in these subgroups to test new drugs and to quickly/economically identify them.

Methods
GEP were performed on 55 Ph-/-/-, 29 Ph+ B-ALL and on 7 donors. We cluster Ph-/-/- GEP data with our validated pipeline, based on CRLF2 upreg and in a top ten-gene list. Ph-/-/- samples were then characterized for the presence of gene fusions, Copy Number Alterations (CNAs) and mutations using different approaches (1385 RNA Panel and/or RNASeq; dMLPA; SNP Array; Target Seq, PCR and 44 WES).

Results
Ph-/-/- WES analysis identified some recurrent mutated genes (NRAS, PAX5, JAK2, TP53, PTPN11, CREBBP) previously reported to be involved in B-ALL, confirming the pivotal roles of these gene in ALL. For the first time we described PKHD1L1 as highly mutated (7.2%; Fig 1A). TP53 was the most mutated gene and that between these genes is the only one associated to a worst OS (p=0.004). The Ph-/-/- fusions rate is of 43% (23/52), denoting that Ph-/-/- are not usually widely characterized. Combining our new Ph-/-/- GEP clustering to SNVs, Fusion and CNA results we identify a defined 2-clusters-subdivision (Gr1 and Gr2). The Gr2 is characterized by CTGF, CRLF2 and CD200 (Gr2=3C-up; Fig 1B) co-overexpression and it represents 14.1% of all B-ALL. The Gr2 GEP is similar to Ph+ one (Fig 1C), similarly to Ph-like. Fusion, CNAs and mutational screening done, detected that “3C-Up” group has a higher frequency of Ph-like associated lesions (primarily CRLF2, JAK2, IL7R mutation or deletion), that mainly affect JAK-STAT pathway. Also IKZF1 and EBF1 del are significantly associated to Gr2 (p=0.003; p=0.016). Gr1 represents 46.9% of all B-ALL and RAS pathway genes are highly affected in this group. Notably p53 pathway is enriched in both groups but with different deregulated genes: CHEK2 is upregulated in the group1 and CDK6 in the Gr2. Preliminary data seems to confirm an higher effect on cell viability of Bosutinib on Gr2 primary cell pt (vs Gr1 pt). Lastly, we develop a cytofluorimetric (IF) a B-ALL panel to quickly detect 3C-Up at diagnosis/relapse. With this test, we confirm that 3C marker co-overexpr. is confirmed at protein level in pt MNCs.

Conclusion
we identified a new signature, related to CRLF2 high expression, to classify Ph-/-/- B- in 2 subgroups. 3C-Up has Ph-like related alterations and high co-expression of CRLF2, CTGF and CD200 that we could easily identify with IF. This new Ph-/-/- subclassification identify new potential therapeutic targets with available drugs (i.e. α-CTGF, α-CD200, CHK2 and CDK6 inhibitors; TKIs already effective on Ph+ and Ph-like) to test. Supported by: AIL, FP7 NGS-PTL project, Harmony.

Session topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): B cell acute lymphoblastic leukemia, Gene expression profile

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