Immunophenotypic Plasticity of Pediatric B Acute Lymphoblastic Leukemia: a Genomic Study
Research Area: Pediatric hematology, oncology and hematopoietic cell&gene therapy
Group Leader
We identified a new subtype of pediatric BCP-ALL, characterized by aberrant expression of antigen CD371 (CD371+) at diagnosis and immunophenotypic (IP) plasticity during therapy [transient myelomonocytic switch-SW; discrepancy between MFC-MRD and PCR-MRD on Day33 (D33-MFC/PCR-MRD discrepancy)]. IP plasticity may compromise the final therapeutic risk group assignment, especially in absence of IGH/TCR receptor rearrangements (IGH/TCRrr) to be used as PCR-MRD marker. Hypotheses on IP plasticity include: 1) blast immaturity with biological potential for myeloid and lymphoid differentiation; 2) blast heterogeneity at diagnosis and subsequent prevalence of resistant subclones sharing genomic features with myelomonocytic cells. Our research aims at i) defining the genomic features of CD371+BCP-ALL at diagnosis; ii) investigating the transcriptomic basis of CD371+BCP-ALL IP plasticity; iii) investigating D33-MFC/PCR-MRD discrepancy. To these aims we will analyze i) at least 24 SMP at diagnosis (50% CD371+) that will undergo WES, GEP, and methylation assay, ii) blast populations from at least 10 de novo CD371+BCPALLs at diagnosis and during therapy (Day8 or Day15) that will be characterized by single-cell RNA sequencing, and we will performed RT-PCR of IGH/TCRrr on sorted populations from at least 3 SMP with D33-MFC/PCR-MRD discrepancy. We expect to confirm the inclusion of CD371+BCP-ALL in DUX4-rearranged ALL GEP subgroup; to confirm IP plasticity hypothesis 1; to detect any genomic features of therapy resistance; to confirm IP plasticity hypothesis 2; to detect any variation of transcriptome after chemotherapy and between different blast populations in the same SMP; to detect IGH/TCRrr positivity in sorted populations. In perspective, GEP will allow discriminating populations sharing IGH/TCRrr, detecting new markers potentially applicable to MFC-MRD.
Group Members
Elena Varotto, Post-doctoral fellows
Giulia Gomiero, PhD students
Selected Publications
Popov A, Buldini B, et al. Prognostic value of minimal residual disease measured by flow-cytometry in two cohorts of infants with acute lymphoblastic leukemia treated according to either MLL-Baby or Interfant protocols. Leukemia. 2020 Jun 1;
Alexander TB, Gu Z, Iacobucci I, Dickerson K, Choi JK, Xu B, Payne-Turner D, Yoshihara H, Loh ML, Horan J, Buldini B, et al. The genetic basis and cell of origin of mixed phenotype acute leukaemia. Nature. 2018 Oct;562(7727):373-379;
Hrusak O, de Haas V, Stancikova J, Vakrmanova B, Janotova I, Mejstrikova E, Capek V, Trka J, Zaliova M, Luks A, Bleckmann K, Möricke A, Irving J, Konatkowska B, Alexander TB, Inaba H, Schmiegelow K, Stokley S, Zemanova Z, Moorman AV, Rossi JG, Felice MS, Dalla-Pozza L, Morales J, Dworzak M, Buldini B, et al. International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood. 2018 Jul 19;132(3):264-276;
Bertaina A, Zecca M, Buldini B, et al. Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood. 2018 Dec 13;132(24):2594-2607;
Dworzak MN, Buldini B, Gaipa G, et al. International-BFM-FLOW-network. AIEOP-BFM consensus guidelines 2016 for flow cytometric immunophenotyping of Pediatric acute lymphoblastic leukemia. Cytometry B Clin Cytom. 2018 Jan;94(1):82-93;
Buldini B, F. Rizzati, R. Masetti, et al. Prognostic significance of flow-cytometry evaluation of minimal residual disease in children with acute myeloid leukaemia treated according to the AIEOP-AML 2002/01 study protocol. Br J Haematol. 2017 Apr;177(1):116-126;
Conter V, Valsecchi MG, Buldini B, et al. Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis. Lancet Haematol. 2016 Feb;3(2):e80-6;
Gaipa G, Cazzaniga G, Valsecchi MG, Panzer-Grümayer R, Buldini B, et al. Time point-dependent concordance of flow cytometry and real-time quantitative polymerase chain reaction for minimal residual disease detection in childhood acute lymphoblastic leukemia. Haematologica. 2012 Oct;97(10):1582-93;
Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grümayer R, Möricke A, Parasole R, Zimmermann M, Dworzak M, Buldini B, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011 Aug 25;118(8):2077-84;
Béné MC, Nebe T, Bettelheim P, Buldini B, et al. Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10. Leukemia. 2011 Apr. Volume: 25(4): 567-574;
Contact
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Phone: +39 049 9640111
Fax: +39 049 9640101
info@irpcds.org
