scholarly journals Acute promyelocytic leukemia: PML/RARα and the leukemic stem cell

Leukemia ◽  
2004 ◽  
Vol 18 (7) ◽  
pp. 1169-1175 ◽  
Author(s):  
E Puccetti ◽  
M Ruthardt
Keyword(s):  
Stem Cell ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Leukemic Stem Cell

The Acute Promyelocytic Leukemia-Associated Fusion Protein PML/RAR Blocks t-RA-Induced Differentiation in a Subset of Cells with Stem Cell Potential.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1175-1175
Author(s):  
Xiaomin Zheng ◽  
Anita Seshire ◽  
Elena Puccetti ◽  
Hilal Gul ◽  
Tim Beissert ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Fusion Protein ◽  
Cell Line ◽  
Acute Promyelocytic Leukemia ◽  
Fusion Proteins ◽  
Side Population ◽  
Promyelocytic Leukemia ◽  
Molecular Remission ◽  
Nb4 Cells

Abstract Acute promyelocytic leukemia (APL) is distinguished from other AMLs by cytogenetic, clinical, as well as biological characteristics. The hallmark of APL is the t(15;17) which leads to the expression of the PML/RAR fusion protein. PML/RAR is the central leukemia-inducing lesion in APL and is directly targeted by all trans retinoic acid (t-RA). Patients suffering from APL undergo complete hematologic but not molecular remission upon treatment with t-RA. Virtually all patients treated with t-RA-monotherapy had a rapid relapse within few months. But in the combination with an anthracycline, such as doxorubicin or idarubicin, t-RA improved the long term outcome of APL-patients dramatically. Nothing is known about why t-RA-monotherapy is unable to eradicate completely the leukemic population and how it increases the response to chemotherapy. In vitro, the exposure of early hemopoietic stem cells (HSCs) to t-RA does not induce differentiation but selects immature progenitors. Moreover, mice lacking the t-RA-specific receptor RARalpha do not exhibit an impairment of granulopoiesis or hemopoiesis. The indication, that t-RA may be involved in the hemopoietic differentiation, is given by the HL-60 cell line which undergoes granulocytic differentiation at the pharmacological dosages (10−6M) of t-RA. Furthermore vitamin A-deficient mice or mice treated with a antagonist of t-RA accumulate more immature granulocytes in the bone marrow. PML/RAR mediates the response of APL blasts to t-RA, but it is completely unclear, which effect t-RA exerts on the PML/RAR-positive leukemic stem cells which maintains the blast population and represents the source of relapse. Therefore we investigated the effect of t-RA on a cell population with stem cell capacity expressing PML/RAR isolated from the APL cell line NB4 as well as from CD34+/CD38- KG-1 cells transfected with PML/RAR. Here we report that i) the NB4 cells engrafted in NOD/SCID mice indicating the presence of a subpopulation with stem cell capacity in NB4 cells; ii) NB4 had a Hoechst 3342 excluding side population (SP) representing about 1% of the whole cell population; iii) t-RA reduced but did not deplete the side population in NB4 cells; iv) the expression of PML/RAR increased CD34+/CD38- population in KG-1 cells from 75% to over 95%; v) t-RA reduced the CD34+/CD38- population from 75% to 3,5% in mock transfected KG-1 confirming its capacity to induce differentiation, whereas in PML/RAR-positive KG-1 cells it led only to a reduction from 98% to a 25%, which still maintain the capacity to engraft in NOD-SCID mice; vi) also the expression of other fusion proteins, such as AML-1/ETO or PLZF/RAR, associated with t-RA-resistant AML-subtypes, increased the percentage of CD34+/CD38- KG-1 cells over 90%, which was reduced by t-RA only to 35% and 19%, respectively. Taken together these data suggest that a subset of early HSC expressing PML/RAR exhibit the same t-RA-resistant phenotype as HSC expressing fusion proteins associated with AML-subtypes which, in contrast to APL, do not respond to t-RA. These data may give an explanation, why APL-patients do not achieve complete molecular remission upon t-RA monotherapy and undergo early relapse.

Treatment of Relapsed Acute Promyelocytic Leukemia by Arsenic-Based Strategies without Hematopoietic Stem Cell Transplantation in Hong Kong: A Seven-Year Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 395-395 ◽  
Author(s):  
Wing Y. Au ◽  
James C. Chim ◽  
Albert K. Lie ◽  
Cyrus R. Kumana ◽  
Anskar Y. Leung ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Promyelocytic Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Promyelocytic Leukemia ◽  
High Morbidity ◽  
Hematopoietic Stem

Abstract Background: The optimal therapy for relapsed acute promyelocytic leukemia (APL) after arsenic trioxide (As2O3)-induced remission is unclear. Hematopoietic stem cell transplantation (HSCT) is associated with high morbidity and mortality. Moreover, lasting remission is observed in many patients who are not candidates for HSCT, owing to advanced age or lack of donors, implying that HSCT is not mandatory for durable remission. We evaluated our results of an As2O3-based, non-HSCT regimen for patients with relapsed APL. Materials and methods: Forty-two consecutive patients (18 men, 24 women, median age: 35 years, 12–72) with relapsed (relapse 1, R1=39, R2=3) APL were treated with an-As2O3 based, non-HSCT regimen. The time from last complete remission (CR) was 22 (6–243) months (mo). Initial treatment was As2O3 (10 mg/day) either intravenously (n=16) or orally (n=28) until CR, followed by idarubicin consolidation (6 mg/m2/day x 9). Twenty-five patients received oral-As2O3 maintenance. Post-As2O3 relapses were treated with oral As2O3 + all-trans retinoic acid (ATRA, 45 mg/m2/day) until CR, followed by maintenance (two weeks of ATRA+As2O3 every 2 mo. for 2 years). Post-As2O3/ATRA relapses were treated with oral As2O3+ATRA+ascorbic acid (1g/day) until CR, followed by consolidation/maintenance with the same regimen (2 weeks every 2 mo. for 2 years). Part of the induction and all of the maintenance therapies were given in the outpatient clinic. Results: Forty-one patients (98%) achieved CR after initial As2O3 treatment. One 72-year old man with XYY syndrome, diabetes and mental retardation died of pneumonia. Thirteen relapses occurred at a median of 15 (6–22) mo. As2O3-maintenance significantly decreased further relapses (3/24 with versus 10/17 without As2O3-maintenance, p=0.003). Two relapses died of cerebral APL before further treatment could be administered. Of eleven patients treated with As2O3+ATRA, 10 achieved CR, 8 of whom have remained in remission (median follow-up: 33 mo.). Two post-As2O3/ATRA relapses achieved CR again with As2O3+ATRA+ascorbic acid, and have remained in remission after maintenance treatment with As2O3+ATRA+ascorbic acid. All patients in continuous remission (n=38) were PML/RARa negative on polymerase chain reaction (sensitivity 10−3 to 10−4). Conclusion: Our regimen resulted in a leukemia-free-survival of 89.3%. The results suggest that an oral and mainly outpatient As2O3-based, non-HSCT strategy is efficacious for relapsed APL. In terms of survival, costs, treatment side effects and patient tolerance, the results appear to be comparable to, if not more favorable than, other treatment options based on high dose chemotherapy, graft-versus-leukemia effect, or anti-myeloid antibody therapy.

scholarly journals Role of Hematopoietic Stem Cell Transplantation in Acute Promyelocytic Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Jaime Sanz ◽  
Pau Montesinos ◽  
Miguel A. Sanz
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Promyelocytic Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Promyelocytic Leukemia ◽  
Controlled Study ◽  
High Dose ◽  
Hematopoietic Stem

The indication of hematopoietic stem cell transplantation (HSCT) in acute promyelocytic leukemia (APL) has evolved historically from a widespread use in front-line therapy during the pre-ATRA era to a virtual rejection of this indication for patients treated with modern treatments. HSCT in first complete remission could only be considered for an extremely small fraction of patients with persistent MRD at the end of consolidation or for those who relapse. In the pre-ATO era, relapsed patients were usually treated with readministration of ATRA and chemotherapy as salvage therapy, generally containing high-dose cytarabine and an anthracycline, followed by further post-remission chemotherapy and/or HSCT. ATO-based regimens are presently regarded as the first option for relapsed APL. The selection of the most appropriate post-remission treatment option for patients in second CR (CR2), as well as the modality of HSCT when indicated, depends on several variables, such as pre-transplant molecular status, duration of first remission, age, and donor availability. Although with a moderate level of evidence, based on recent retrospective studies, autologous HSCT would be at present the preferred option for consolidation for patients in molecular CR2. Allogeneic HSCT could be considered in patients with a very early relapse or those beyond CR2. Nevertheless, the superiority of HSCT as consolidation over other alternatives without transplantation has recently been questioned in some studies, which justify a prospective controlled study to resolve this still controversial issue.

scholarly journals Highly purified primitive hematopoietic stem cells are PML-RARA negative and generate nonclonal progenitors in acute promyelocytic leukemia

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2154-2161 ◽  
Author(s):  
AG Turhan ◽  
FM Lemoine ◽  
C Debert ◽  
ML Bonnet ◽  
C Baillou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Acute Promyelocytic Leukemia ◽  
Cell Sorting ◽  
Fusion Gene ◽  
Promyelocytic Leukemia ◽  
Pcr Analysis ◽  
Cell Populations ◽  
Rt Pcr ◽  
Hematopoietic Stem

The hierarchical level of stem cell involvement in acute promyelocytic leukemia (APL) characterized by the pathognomonic PML-RARA fusion gene is unknown. To determine if the cells of the primitive hematopoietic stem cell compartment are involved in the leukemic process, we have used molecular and cell sorting techniques in peripheral blood and bone marrow (BM) cells at diagnosis from three patients with APL and t(15; 17). In two of them, clonality analysis was also possible using the BstXI polymorphic site of the PGK gene. The PML-RARA fusion gene was readily identified by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of BM cells obtained at diagnosis in all three patients. These same samples were then used to sort CD34+ cells and their CD38+ and CD38-subsets by fluorescence-activated cell sorting. In both female patients, CD34+/CD38+ and CD34+/CD38- cell fractions were polyclonal using PCR, whereas a monoclonal pattern was identified at the BM sample obtained at diagnosis either by Southern blotting or by PCR. Because of the high sensitivity of the PCR analysis, the polyclonal pattern of these cell populations could mask the presence of a minor clone. To detect this clone, we preformed RT-PCR analysis for t(15; 17). In one female patient, the abnormal PML-RAR fusion gene was found only in the more mature CD34+/CD38+ cell fraction using a nested PCR approach, whereas the polyclonal CD34+/CD38- fraction was PML-RARA negative. These findings were confirmed in a third patient with APL in whom the PML-RARA transcripts were absent in the CD34+/CD38- cell fraction. To study the clonality at the level of clonogenic progenitors, we used in one patient PGK analysis by PCR of individual burst-forming units-erythroid and colony-forming units-granulocyte- macrophage obtained from the CD34+/CD38- and CD34+/CD38+ cell populations at diagnosis and from the BM sample obtained during remission. The two highly purified cell populations gave rise to morphologically normal colonies clonal for both the BstXI site containing (A) and the BstXI site lacking (B) PGK allelles, indicating their polyclonal content, a pattern that was also found in clonogenic progenitors obtained at remission. These findings strongly suggest that the primitive hematopoietic stem cells as defined by the CD34+/CD38- antigens are not involved by the neoplastic process in APL. These results may have important implications for autografting strategies of retinoic acid/chemotherapy-resistant or relapsed patients.

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