post-transplantation relapses

The Role of BAALC-Expressing Leukemia Precursor Cells in the Pathogenesis of Myelodysplastic Syndromes

AUTOIMMUNE THROMBOCYTOPENIA , ,

NN Mamaev, MV Latypova, AI Shakirova, TL Gindina, MM Kanunnikov, NYu Tsvetkov, IM Barkhatov, SN Bondarenko, MD Vladovskaya, EV Morozova

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Prof. Nikolai Nikolaevich Mamaev, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: nikmamaev524@gmail.com

For citation: Mamaev NN, Latypova MV, Shakirova AI, et al. The Role of BAALC-Expressing Leukemia Precursor Cells in the Pathogenesis of Myelodysplastic Syndromes. Clinical oncohematology. 2022;15(1):62–8. (In Russ).

DOI: 10.21320/2500-2139-2022-15-1-62-68

ABSTRACT

The present paper provides evidence for a high detection rate of BAALC gene overexpression, also combined with WT1 gene overexpression, in patients with myelodysplastic syndromes (MDS) and FISH-verified chromosome defects. The BAALC and WT1 gene expression profiling in 16 MDS patients (6 out of them received allogeneic hematopoietic stem cell transplantation) showed an increased BAALC expression in 14 patients. The expression level in 2 patients was near the cut-off. Low expression levels were identified in a female patient with isolated 5q deletion in karyotype and also with its combination with complex karyotype. On the other hand, the highest expression levels were reported in patients with normal karyotype and 3q26 locus rearrangement, which was associated with EVI1 gene overexpression. Since the BAALC expression level, at least in patients with the major (except for М3 and М7) FAB-variants of acute myeloid leukemias (AML), was closely associated with BAALC-producing precursor cells of leukemia clone, a profound study of this phenomenon in MDS patients seems to be important for understanding the finest mechanisms underlying the pathogenesis of AML and AML relapses on the level of precursor cells.

Keywords: myelodysplastic syndromes, BAALC and WT1 genes, overexpression, post-transplantation relapses, BAALC-producing precursor cells, pathogenesis, prognosis.

Received: July 7, 2021

Accepted: November 4, 2021

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Статистика Plumx английский

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    [Mamaev NN, Shakirova AI, Barkhatov IM, et al. Crucial Role of BAALC–Expressing Progenitor Cells in Emergence and Development of Post-Transplantation Relapses in Patients with Acute Myeloid Leukemia. Clinical oncohematology. 2020;13(1):75–88. doi: 10.21320/2500-2139-2020-13-1-75-88. (In Russ)]
  7. Mamaev NN, Shakirova AI, Barkhatov IM, et al. Crucial role of BAALC-expressing leukemic precursors in origin and development of posttransplant relapses in patients with acute myeloid leukemias. Int J Hematol. 2020;8(6):127–31. doi: 10.15406/htij.2020.08.00240.
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    [Mamaev NN, Shakirova AI, Morozova EV, Gindina TL. EVI1-Positive Leukemias and Myelodysplastic Syndromes: Theoretical and Clinical Aspects (Literature Review). Clinical oncohematology. 2021;14(1):103–17. doi: 10.21320/2500-2139-2021-14-1-103-117. (In Russ)]
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Analysis of Karyotype Aberrations in Children and Adolescents with Post-Transplantation Relapses of Acute Leukemia

BONE MARROW TRANSPLANTATION , ,

T.L. Gindina, N.N. Mamaev, E.N. Nikolaeva, I.A. Petrova, S.N. Bondarenko, A.L. Alyanskii, N.V. Stancheva, O.A. Slesarchuk, M.Yu. Aver’yanova, L.S. Zubarovskaya, B.V. Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Leonidovna Gindina, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

For citation: Gindina TL, Mamaev NN, Nikolaeva EN, et al. Analysis of Karyotype Aberrations in Children and Adolescents with Post-Transplantation Relapses of Acute Leukemia. Clinical oncohematology. 2015;8(4):420–427 (In Russ).

DOI: 10.21320/2500-2139-2015-8-4-420-427

ABSTRACT

Aim. To analyze the karyotype aberrations at the relapse after allogeneic HSCT (alloHSCT) in children and adolescents with acute leukemias, in order to evaluate their relation with disease-free survival and overall survival (OS) rates after the relapse and to identify prognostic groups of patients based on clinical and cytogenetic characteristic of a tumor.

Methods. Cytogenetic investigations were performed in 30 children and 15 adolescents (26 males and 19 females aged from 1.2 to 21 years; median age 10 years) with a post-transplant relapse (PTR) of acute myeloid leukemia (n = 29) and acute lymphoblastic leukemia (n = 16). The analysis of aberrating chromosomal abnormalities was performed by comparison of the karyotypes in relapse with those before the alloHSCT.

Results. Karyotype aberrations in PTR were observed in 29 (64 %) patients. 2 and more abnormal cytogenetic clones were observed in 10 (34 %) patients with PTR. Additional chromosomal aberrations acquired in PTR were related primarily to chromosomes 1, 11 and 19. OS after the relapse was higher in patients with alloHSCT performed during the remission and with one abnormal cytogenetic clone in PTR. Based on this, we formed three prognostic groups: the first group consisted of 8 (18 %) patients with 2 adverse factors and median 40-day OS after relapse; the second group included 20 (44 %) patients with 1 adverse factor and median OS after PTR equal to 152 days, and the 4-year survival was 16 %; the third group included 17 (38 %) patients without the above negative factors and median OS after relapse equal to 549 days, and the 4-year survival was 31 %. The multivariate analysis showed that the number of abnormal cytogenetic clones in leukemic population is an independent predictor of OS after PTR.

Conclusion. The presence of leukemic population of ³ 2 abnormal cytogenetic clones is the most important prognostic factor affecting the OS in PTR patients. Since the clonal evolution of the karyotype may be associated with the use of cytotoxic drugs in the therapy of acute leukemia in children and adolescents with indications for alloHSCT, the latter should be done as soon as possible and non-myeloablative conditioning regimen should be preferred.

Keywords: pediatric acute leukemias, post-transplantation relapses, clonal cytogenetic evolution.

Received: June 13, 2015

Accepted: November 8, 2015

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  7. Cho Y, Chi H, Park S, et al. Comparative analysis of cytogenetic evolution patterns during relapse in the hematopoietic stem cell transplantation and chemotherapy settings of patients with acute leukemia. Blood. 2013;122(21):1320.
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  9. Гиндина Т.Л., Мамаев Н.Н., Бархатов И.М. и др. Сложные повреждения хромосом у больных с рецидивами острых лейкозов после аллогенной трансплантации гемопоэтических стволовых клеток. Терапевтический архив. 2012;8:61–6.
    [Gindina TL, Mamaev NN, Barhatov IM, et al. Complex chromosome damages in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantations. Terapevticheskii arkhiv. 2012;8:61–6 (In Russ)]
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  11. Gindina T, Mamaev N, Bondarenko S, et al. Complex aberrant karyotype in patients with post-transplant relapses of acute myeloid and lymphoid leukemias evaluated by serial cytogenetic assays, including mFISH. Blood. 2014;124(21):5313.

Complex Chromosomal Aberrations in Patients with Post-Transplantation Relapses of Acute Leukemias: Clinical and Theoretical Aspects

MYELOID TUMORS , ,

TL Gindina, NN Mamaev, SN Bondarenko, NV Semenova, EN Nikolaeva, ME Vlasova, NV Stancheva, OA Slesarchuk, VN Vavilov, EV Morozova, AL Alyanskii, BV Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Leonidovna Gindina, PhD, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: tatgindina@gmail.com

For citation: Gindina TL, Mamaev NN, Bondarenko SN, et al. Complex Chromosomal Aberrations in Patients with Post-Transplantation Relapses of Acute Leukemias: Clinical and Theoretical Aspects. Clinical oncohematology. 2015;8(1):69–77 (In Russ).

ABSTRACT

Objective. To analyze the incidence of a complex karyotype in patients with post-transplantation relapses of acute myeloid leukemias and to evaluate preliminary treatment results before and after bone marrow transplantation in order to elaborate optimal approaches to the treatment of this disease.

Methods. Cytogenetic investigations (including fluorescent in situ hybridization [FISH]) were performed in 100 patients (53 males, 47 females aged from 1 to 60; median — 23 years) with post-transplantation relapses of acute myeloid leukemias (AML) (n = 61) and acute lymphoblastic leukemia (ALL) (n = 39).

Results. Aberrant karyotypes were found in 90 % of AML and 97 % of ALL patients. The incidence of acute leukemias (AL) with complex karyotypes (CK) was significantly higher in ALL patients than that in the AML group (67 % vs 36 %; p = 0.002). At that, the percentage of CK with 4 and more chromosome abnormalities per cell in ALL patients aged 1–18 years was also significantly higher than that in AML patients (60 % vs 30 %; p = 0.03). Besides, this difference was observed in the CK+ proportion between ALL and AML groups. Transplantation was performed during the active phase of the disease (i.e. after remission) in 75 % vs 55 %, respectively (p = 0.003).

Conclusions. Serial cytogenetic investigations showed that CKs before transplantation and in PTR are closely related, thus confirming their clonal nature. Therefore, it may be assumed that karyotype complication achieved by the PTR can be caused by both chemotherapy performed at early stages of acute leukemia and pre-transplant conditioning regimes. In this case, further increase of the chemotherapeutic intensity in order to prevent and treat expected PTRs in patients with CK+ acute leukemias seems to be unreasonable. In this connection, infusion of donor lymphocytes, administration of hypomethylating agents or medicines with target mechanism of action should be used for management of AML patients during the post-transplant period.

Keywords: acute leukemias, post-transplantation relapses, complex karyotype.

Received: September 2, 2014

Accepted: November 13, 2014

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