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29 October 2001, Volume 20, Number 49, Pages 7216-7222
Table of contents    Previous  Article  Next   [PDF]
The theory of APL
Francesco Piazza, Carmela Gurrieri and Pier Paolo Pandolfi

Molecular Biology Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, 1275 York Avenue, New York, New York, NY 10021, USA

Correspondence to: P P Pandolfi, Molecular Biology Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, 1275 York Avenue, New York, New York, NY 10021, USA. E-mail: p-pandolfi@ski.mskcc.org


Acute promyelocytic leukemia (APL) is associated with reciprocal and balanced chromosomal translocations always involving the Retinoic Acid Receptor alpha (RARalpha) gene on chromosome 17 and variable partner genes (X genes) on distinct chromosomes. RARalpha fuses to the PML gene in the vast majority of APL cases, and in a few cases to the PLZF, NPM, NuMA and STAT5b genes. As a consequence, X-RARalpha and RARalpha-X fusion genes are generated encoding aberrant fusion proteins that can interfere with X and/or RARalpha function. Here we will review the relevant conclusions and the open questions that stem from a decade of in vivo analysis of APL pathogenesis in the mouse in transgenic and knock-out models. Oncogene (2001) 20, 7216-7222.


APL; transgenic mice; KO mice; animal models; tumor metamorphosers


Acute promyelocytic leukemia (APL), the M3 subtype of the FAB classification of acute myeloid leukemia (AML), is associated with reciprocal and balanced translocation always involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17, which translocates to the PML gene (promyelocytic leukemia gene, originally named myl) on chromosome 15 in the vast majority of APL cases (de The et al., 1991; Goddard et al., 1991; Kakizuka et al., 1991; Pandolfi et al., 1991). In rare cases RARalpha fuses to the promyelocytic leukemia zinc finger (PLZF) gene, to the nucleophosmin (NPM) gene, to the nuclear mitotic apparatus (NuMA) gene and to the signal transducer and activator of transcription 5b (STAT5b) gene located on chromosome 11, 5, 11, or 17, respectively (Chen et al., 1993; Redner et al., 1996; Wells et al., 1997; Arnould et al., 1999). The various translocations result in the formation of X-RARalpha and RARalpha-X fusion genes and the co-expression of their products in the APL blasts. Although rare, these APL variant translocations have been extremely informative, pointing at possible molecular and biological similarities and differences among the various fusion proteins. As an example, while the various chromosomal translocations are associated with leukemias that can be morphologically recognized as APL, on the other hand, distinct translocations are associated with distinct responses to treatment. The vast majority of APL respond in fact to treatment with all-trans retinoic acid (ATRA), by contrast t(11;17)/PLZF-RARalpha and possibly t(17;17)/STAT5b-RARalpha APL show little or no response to treatment with ATRA and poor response to chemotherapy (Licht et al., 1995; Arnould et al., 1999). In view of the fact that the RARalpha gene always breaks within the same intron, the various X-RARalpha proteins are coherent in the RARalpha moiety but do not bear structural similarities in the X moiety. The X moiety could thus mediate the aforementioned differential response to treatment. The RARalpha portion is able to mediate heterodimerization with RXRs as well as DNA and ligand binding through the DNA and retinoic acid (RA) binding domains, respectively. (Perez et al., 1993). Therefore, the X-RARalpha fusion products always retain the ability to interfere with the RAR/RXR pathways. However, the various X-RARalpha proteins also invariably display the capacity of heterodimerizing with the respective X proteins (e.g. PML-RARalpha with PML etc.). This is due to the fact that X proteins can homodimerize/oligomerize in the nucleus and that the regions which can normally mediate X proteins homodimerization are retained in the various X moieties fused to RARalpha (Liu and Chan, 1991; Perez et al., 1993; Bardwell and Treisman, 1994; Redner et al., 1996; Wells et al., 1997; Arnould et al., 1999). Thus, X-RARalpha can simultaneously interfere, at least on paper, with both X and RARalpha pathways.

The RARalpha-X fusion protein also retains critical regions from the COOH-moiety of the various X proteins, which fuse to the A transacting domain of RARalpha and could therefore play an active role in APL pathogenesis.

Definitive answers concerning the oncogenic role of the APL fusion proteins and the normal function of the various X genes and how it is deregulated in APL is being obtained from a detailed analysis performed in transgenic and knock-out (KO) mice. However, while this analysis has addressed some of the immediate and obvious questions concerning APL pathogenesis, several critical aspects still remain to be understood. Furthermore, novel intriguing questions have emerged that will need to be addressed in the future. We will here briefly summarize these achievements, but also focus our attention on the open questions, which will direct APL research in the next few years.

A decade of APL genetics in the mouse

Although the t(15;17) translocation of APL was molecularly cloned 10 years ago by now, the first manuscripts describing the oncogenic potential of the PML-RARalpha fusion protein in transgenic mice (TM) were published only 6 years later (Grisolano et al., 1997; He et al., 1997; Brown et al., 1997). This was due to the fact that ubiquitous and unrestricted expression of the fusion gene results in embryonic lethality (He et al., 1997; our unpublished observation). The expression of PML-RARalpha in early hemopoietic progenitors or in mature myeloid cells did not result in leukemia either (P Greer, personal communication; Early et al., 1996). It is only when the expression of the transgene was directed and restricted to the myeloid promyelocytic compartment that it was possible to draw important conclusions concerning the role of the various X-RARalpha and RARalpha-X fusion proteins in APL pathogenesis. The almost contemporary generation of KO mice and cells, where the PML and PLZF genes were inactivated by homologous recombination, has also been extremely informative, not only in elucidating the function of these genes, but also in assessing the consequences of the reduction to heterozygosity or the complete inactivation of X gene function in TM harboring APL fusion proteins. The combined analysis of TM and KO mice and primary cells derived from these mutants has allowed us to reach important conclusions, which we discuss in the next paragraphs.

(i) X-RARalpha proteins are necessary but not sufficient to cause leukemia, are biologically distinct RARalpha mutants and directly mediate differential response to RA

Characterization of PML-RARalpha and PLZF-RARalpha TM in which the expression of the fusion gene is under the control of a human Cathepsin-G (hCG) minigene, driving the promyelocytic specific transgene expression, has revealed that the X-RARalpha fusion proteins play a critical role in leukemogenesis as well as in determining responses to RA in APL, since PLZF-RARalpha mice develop RA-resistant leukemia (He et al., 1998), while PML-RARalpha mice develop RA-responsive leukemia (Grisolano et al., 1997; He et al., 1997). The comparative analysis of the phenotypes in PML-RARalpha and PLZF-RARalpha TM further supports the notion that X-RARalpha molecules do not represent identical RARalpha mutants since both hemopoiesis and leukemogenesis in these mice are biologically distinct: PML-RARalpha TM develop APL leukemia, while PLZF-RARalpha TM develop leukemia which lacks the block of differentiation at the promyelocytic stage characteristic of APL, displaying features reminiscent of human chronic myelogenous leukemia (CML) rather than of human APL (He et al., 1998).

Similar results have been obtained by Brown et al. (1997) utilizing the macrophage-inhibiting factor related protein-8 (hMRP8) expression cassette to direct PML-RARalpha expression highly in early myeloid progenitors but also in more mature myeloid cells of the transgenic animal (Lagasse and Weissman, 1994).

This in vivo analysis also demonstrates that X-RARalpha proteins are necessary but not sufficient for leukemogenesis, since full-blown leukemia is always preceded by a long latency varying between 6 months to 1 year (Grisolano et al., 1997; He et al., 1997, 1998; Brown et al., 1997). In the preleukemic phase, however, the various transgenic lines display, at 100% penetrance, aberrant hemopoiesis and a myeloproliferative disorder characterized by the slow and progressive accumulation of myeloid cells in the spleen and in the bone marrow. Thus, additional genetic events are likely accumulating in order to trigger full-blown leukemia in X-RARalpha TM. In human APL blasts, one of such events could be represented by the RARalpha-X fusion protein (see also following paragraphs).

More recently, Kogan et al. (2000) generated TM harboring a PML-RARalpha mutant (M4) that can no longer bind RA, placed under the control of the hMRP8 gene promoter. These TM developed an APL-like RA-resistant leukemia, thus strongly suggesting that ligand dependent transactivation by the PML-RARalpha fusion protein is not required for leukemogenesis.

(ii) RARalpha-X proteins are not sufficient for, but do play a critical role in leukemogenesis

Comparative characterization of RARalpha-X TM has revealed an important role for these molecules in APL leukemogenesis. RARalpha-PML TM do not develop leukemia nor alteration of the myeloid cellular compartment, whereas RARalpha-PLZF TM display aberrant hemopoiesis characterized by a myeloproliferative disorder, which results in the expansion of the myeloid cellular compartment without an apparent block in myeloid differentiation, often resulting in splenomegaly, but never in full blown leukemia (Pollock et al., 1999; He et al., 2000). In PML-RARalpha/RARalpha-PML double TM, the RARalpha-PML transgene increases the penetrance of leukemia, thus acting as a classic tumor modifier (Pollock et al., 1999). Strikingly, RARalpha-PLZF activity, in PLZF-RARalpha/RARalpha-PLZF double TM, metamorphoses the CML phenotype observed in PLZF-RARalpha. PLZF-RARalpha/RARalpha-PLZF double TM develop leukemia with features of human APL, such as moderate leukocytosis and the characteristic promyelocytic block in myeloid differentiation. Surprisingly, leukemia onset in PLZF-RARalpha/RARalpha-PLZF double TM is by contrast unaffected and still leukemia is preceded by a long preleukemic phase (He et al., 2000). Thus, RARalpha-X plays an important role in APL leukemogenesis acting as tumor modifiers (RARalpha-PML) and/or tumor metamorphosers (RARalpha-PLZF) respectively. The additional implication of this analysis is that, if these molecules are not expressed, as it seems to be the case in 30% of t(15;17) APL and very rarely in t(11;17) APL, their function could be vicariated by additional, yet unknown, genetic events. Lastly, it is formally possible that the sole expression of one of the two APL products may cause a leukemia/myeloproliferative disorder other than APL.

However, possibly the most relevant implication of these findings is that they genetically unravel the 'qualitative nature' of the multi-step process towards leukemogenesis. In fact, the phenotype observed in the PLZF-RARalpha/RARalpha-PLZF double TM cannot simply be regarded as the mere addition of the phenotypes observed in the single TM, since neither of these mutants display the characteristic block of differentiation at the promyelocytic stage (Figure 1). APL in double TM is instead the qualitatively novel biological outcome of two concomitant aberrant activities affecting distinct molecular pathways (see also following paragraphs) (He et al., 2000).

(iii) X molecules are involved in the control of the transduction of the cell mitogenic and survival signals

Analysis of PML-/- and PLZF-/- mice and cells has in the last few years, corroborated the notion that the blockade or the interference with pathways normally regulated by these molecules can indeed play a critical role in APL pathogenesis. Primary PML KO cells such as mouse embryonic fibroblasts (MEFs) or primary thymocytes display a marked proliferative advantage (Wang et al., 1998a). Furthermore, PML-/- cells of various histological origins including hemopoietic cells and PML-/- mice are protected from multiple apoptotic stimuli such as for instance ionizing radiation (Wang et al., 1998b). The PML pro-apoptotic ability has also been demonstrated in overexpression studies (Quignon et al., 1998). PML has been found to modulate both p53 dependent (Fogal et al., 2000; Guo et al., 2000) and independent (Torii et al., 1999; Zhong et al., 2000) apoptotic pathways. PML inactivation markedly impairs cellular senescence induced by oncogenic Ras (Pearson et al., 2000; Ferbeyre et al., 2000), and renders the cells genetically unstable (Zhong et al., 1999b). Finally, PML-/- mice are more susceptible to tumorigenesis when challenged with carcinogens (Wang et al., 1998a).

More recently, analysis of PLZF-/- mice and cells revealed that the inactivation of this gene can also result in a proliferative and survival advantage throughout embryonic development (Barna et al., 2000). It remains to be seen if the same is true in hemopoietic myeloid cells.

Thus, inactivation of the X genes in the mouse is uncovering functional commonalities between the partners of RARalpha involved the various APL associated chromosomal translocations. X functions may be deregulated in APL as a consequence of the aberrant fusion protein activity.

(iv) X and RAR/RXR pathways are interrelated

Analysis of PML-/- mice and cells has also allowed the demonstration that surprisingly PML is required for the differentiating and growth inhibitory activities of RA. Induction of myeloid differentiation and the ability of RA to induce growth arrest in MEFs are markedly impaired in PML-/- cells and mice (Wang et al., 1998a). PML can act as a ligand-dependent coactivator of RXRalpha/RARalpha through its ability to interact with Tif1alpha and CBP. In PML-/- cells, the RA-dependent induction of genes, such as RARbeta2, and the ability of Tif1alpha and CBP to act as transcriptional coactivators upon RA are impaired (Zhong et al., 1999a)

All together these data demonstate that X and RARalpha pathways can cross talk (Figure 2) and that PML-RARalpha can disrupt the RA-dependent activity of a tumor-growth suppressive transcription complex in a dominant negative manner at multiple levels, resulting in growth advantage and RA unresponsiveness.

(v) The functional interference of X-RARalpha and RARalpha-X with X and RAR/RXR pathways is critical for APL leukemogenesis

As aforementioned, X-RARalpha can interfere, at least theoretically, with X and RARalpha pathways. It is becoming apparent that this property is also shared by some if not all the RARalpha-X fusion proteins. For instance, RARalpha-PLZF can act as a putative dominant negative PLZF mutant. This is due to its ability to bind the PLZF binding site through seven out of the nine zinc-fingers of the Krüppel type that constitute the PLZF DNA binding domain having lost, however, the transcriptional repressive ability of PLZF (He et al., 2000). PLZF transcriptional repression is mediated by the POZ domain that, in RARalpha-PLZF, is replaced by one of the transacting domain of RARalpha.

Furthermore, if the tenet that X-RARalpha and RARalpha-X function can interfere with X and RARalpha pathways is correct, in human APL blasts the oncogenic function of the various fusion proteins can be greatly facilitated by the reduction to heterozygosity of X and RARalpha in view of the fact that one allele of these genes is involved in the chromosomal translocation.

The availability of PML-/- and PLZF-/- mutants as well as of other X and RARalpha-/- mutants is fundamental for addressing these aspects, since, if this is the case, the reduction to heterozygosity or the inactivation of PML and other X proteins or RARalpha should accelerate/exacerbate leukemogenesis by the various fusion proteins in TM.

Indeed, crosses of PML-RARalpha TM with PML-/- mice or PLZF-RARalpha TM with PLZF-/- mice have been extremely informative and totally supported this notion. The progressive reduction of the dose of PML resulted in a dramatic increase in the incidence of leukemia, and in an acceleration of leukemia onset in PML-RARalpha TM. Furthermore, in hemopoietic cells from PML-RARalpha TM, PML inactivation resulted in impaired response to differentiating agents such as RA and vitamin D3 as well as in a marked survival advantage upon pro-apoptotic stimuli. These results demonstrated that PML acts in vivo as a tumor suppressor by rendering the cells resistant to pro-apoptotic and differentiating stimuli and that the functional impairment of PML by PML-RARalpha is a critical event in APL pathogenesis (Rego et al., 2001). The data obtained by crossing PLZF-RARalpha TM with PLZF-/- mice totally supported the notion that RARalpha-PLZF can act as a dominant negative RARalpha mutant and suggested once again that PLZF haploinsufficiency is critical for APL pathogenesis. In fact, PLZF-/-/PLZF-RARalpha mutants develop APL-like leukemia indistinguishable from the one observed in PLZF-RARalpha/RARalpha-PLZF double TM (He et al., 2000).

Open questions and novel directions

(i) Multiple hits in APL pathogenesis?

The long latency observed in leukemia mouse models of APL, even in double TM harboring X-RARalpha and RARalpha-X fusion genes, strongly suggests that additional genetic events may cooperate with the APL specific fusion proteins towards leukemogenesis. The same events could participate in leukemogenesis in human APL. The identification of such mutated genes is therefore crucial to fully dissect APL pathogenesis and to optimize therapy on the basis of this novel molecular information. Several technological approaches are now available that render the identification of these additional genetic hits possible. First of all, spectral karyotyping (SKY), a more sensitive karyological technique, has already allowed Zimonjic et al. (2000) to demonstrate that leukemic cells from PML-RARalpha TM do harbor multiple recurrent chromosomal abnormalities. It will be interesting to see whether various fusion proteins lead to the accumulation of similar or distinct molecular lesions. Also, it will be of paramount importance to define the chronology by which these events accumulate during the pre-leukemic phase. Finally, these recurrent lesions will need to be molecularly characterized. In this respect, the complete sequence of the mouse genome and the parallel use of novel techniques such as comparative genomic hybridization (CGH) microarray techniques will be of extraordinary help to facilitate the identification of genes lost or amplified in leukemia progression (Albertson et al., 2000). These studies could also be accompanied by conventional cDNA/oligo array analysis to study if/how gene expression profile changes throughout disease progression in APL TM (see also below). This approach, performed in parallel with SKY and CGH microrray analyses, will point at genes whose expression is lost or aberrantly increased throughout disease evolution because of chromosomal rearrangements.

(ii) X-RARalpha and RARalpha target genes

Some of the critical biochemical properties, shared by the various X-RARalpha fusion proteins, have been recently elucidated, such as their ability to act as potent and dominant negative transcriptional repressors of the wild-type RARalpha, in view of an aberrant affinity for transcriptional co-repressors and histone deacetylases (He et al., 1998; Grignani et al., 1998; Lin et al., 1998). However, albeit intriguing, the biological implications of these findings are in some way limited by the fact that only very few RARalpha target genes have been so far identified. Even more so, since only to a limited subset of them such as, for instance, p21WAF1/CIP1 and tranglutaminase type II, a distinct biological activity has been attributed (Liu et al., 1996, 2000; Ruthardt et al., 1997; Casini and Pelicci, 1999). Thus, the identification of RARalpha target genes and of genes deregulated by the aberrant transcriptional activity of the X-RARalpha oncoprotein is a major and essential future undertaking.

Furthermore, the data emerging from the in vivo analysis in TM have underscored the distinct biological roles of the X-RARalpha fusion proteins. In fact, these molecules do cause distinct hematological malignancies in TM such as APL-like leukemia in PML-RARalpha TM and CML-like leukemia in PLZF-RARalpha TM (He et al., 1997, 1998). However, the various fusion proteins are identical in their RARalpha moiety and can bind DNA through an intact RARalpha DNA binding domain. Thus, their differential biological behavior has to be conferred by the X moiety. In this respect two models can be entertained: (i) the X moiety confers a distinct DNA binding specificity to the fusion protein which could in turn deregulate distinct, albeit overlapping, gene sets (Figure 3); (ii) alternatively, the various fusion proteins could deregulate the same set of genes, but their differential repressive/activating ability on distinct promoters could result in different biological outcomes.

To address these open and important questions, once again, microarray technology applied to transgenic models of APL will be of tremendous utility.

(iii) The biochemical function of RARalpha-X

As discussed above, the presence of RARalpha-X may play a fundamental role in determining the distinctive biological and clinical features of APL. However, in spite of this evidence, little is known concerning the biochemical role or the target genes of the various RARalpha-X fusion proteins.

RARalpha-PLZF retains the ability to bind to PLZF DNA binding sites although its DNA binding specificity may be altered with respect to the native PLZF protein. The set of genes normally regulated by PLZF could thus be targeted and deregulated.

By contrast the function of the other RARalpha-X fusion proteins is still unknown. As RARalpha-PLZF, RARalpha-PML retains one of the RARalpha transactivation domain fused to the COOH terminus of PML which can mediate protein-protein interactions (Guo et al., 2000). Thus, at least on paper, RARalpha-PML could interfere with PML function. Since RARalpha-PML can exacerbate leukemogenesis in PML-RARalpha TM it could be proposed that this protein confers to the system further survival/proliferative advantage. Alternatively, RARalpha-PML could affect genomic stability perhaps increasing the rate of additional genetic hits and worsening the features of the disease.

(iv) X molecules: common biological properties or converging pathways?

Although the various APL specific translocations involve distinct RARalpha partners these leukemias can be recognized as similar clinical entities. This suggests that either the X pathway is irrelevant to the leukemogenic process or the various X genes products should share common biological functions. As mentioned in the previous paragraphs, this could indeed be the case: X gene inactivation could contribute for instance survival and proliferative advantage to the leukemic blasts. Notwithstanding this preliminary analysis, substantial efforts have still to be made in order to determine the function of the various X genes, to identify their target genes and the pathways that they regulate. There is, however, a further intriguing possibility that is worth exploring genetically: X proteins could control common biochemical pathways/target genes (Figure 4). This is supported for instance by the findings that PML and PLZF can colocalize in discrete subnuclear regions and are found to physically interact (Koken et al., 1997). The availability of X-/- mice will allow testing if this notion holds true in vivo. X mutants could in fact be intercrossed to determine if the resulting phenotype supports the notion of a genetic interaction between the two molecules or if, on the contrary, the double mutant simply displays an additive phenotype with respect to the one observed in the single mutants.

(v) Will a detailed modeling of APL in the mouse guide our therapeutic intervention?

Mouse models of cancer will allow in the future the optimization of therapeutic strategies tailored to specifically antagonize the molecular activities of oncogenic events engineered in the mutant animal. This critical information will next be translated in formal clinical trials in human cancer patients. In APL this in vivo approach in mouse models has already had an important pay off in our ability to optimize therapeutic intervention modalities in human APL. For instance, Rego et al. (2000) have demonstrated that leukemia in PML-RARalpha or PLZF-RARalpha TM respond differentially to Arsenic Trioxide (As2O3), and that this drug failed to induce the degradation of the PLZF-RARalpha fusion protein, as previously shown by Koken and others in blasts from a human t(11;17) APL patient (Koken et al., 1999), thus suggesting that As2O3, may not be effective in the treatment of t(11;17) APL cases. More importantly, in mouse models of PML-RARalpha APL, ATRA and As2O3 have been found to synergize, which prompted testing the association of these two compounds in the treatment of human t(15;17) APL (Lallemand-Breitenbach et al., 1999; Rego et al., 2000). Finally, APL transgenic models have been instrumental in testing the efficacy of transcription therapy with histone deacetylase inhibitors (HDAIs) (Pandolfi, 2001).


Thus, important progress has been made, in the last few years, in dissecting the genetics of APL in vivo in engineered mouse mutants as well as in vitro in cells derived from these animals. All together the data that stem from this analysis allow the proposal of a unified model by which the various X-RARalpha and RARalpha-X fusion proteins play a critical and cooperative role in APL leukemogenesis (Figure 5). These molecules may exert their aberrant activities through the concomitant interference on cross-talking X and RARalpha pathways. While, to date, the involvement of the RARalpha gene and pathway seems to be a prerequisite for APL leukemogenesis, it remains to be seen whether novel additional RARalpha partners (Xn) will be found in the future. Although X-RARalpha and RARalpha-X appear to be critical players in APL pathogenesis they may not be sufficient for leukemogenesis. Additional genetic events, yet to be characterized, probably cooperate with the fusion proteins towards full-blown APL.

If, on the one hand the proposal of a unified theory for APL pathogenesis may have some utility for directing future APL research, on the other hand mouse models of APL are also corroborating the notion that this leukemia, as a clinical and biological entity, is much more heterogeneous than we had originally anticipated and that, more importantly, distinct molecular lesions result in differential response to therapy. This notion will allow us in the near future to tailor therapeutic intervention according to a detailed characterization of the distinctive molecular features of each APL patient.


This work is supported by the NCI, the De Witt Wallace Fund for Memorial Sloan-Kettering Cancer Center, the Mouse Model of Human Cancer Consortium (MMHCC) and NIH Grants to PP Pandolfi and the Lymphoma & Leukemia Society of which PP Pandolfi is a Scholar. Finally, we are indebted to all the past and present members of the laboratory of Molecular and Developmental Biology (MADB) at the Memorial Sloan-Kettering Cancer Center, working on APL and related subjects.


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Figure 1 The qualitative nature of the multistep process towards APL. Double X-RARalpha/RARalpha-X TM display a phenotype distinct from the respective single TM. Phenotypes A in PLZF-RARalpha and B in RARalpha-PLZF single TM are not merely additive. Phenotype C in double TM is instead a distinct and qualitatively novel biological outcome: the result of two concomitant aberrant activities affecting distinct molecular pathways

Figure 2 X and RARalpha pathways are interrelated. Induction of myeloid differentiation and the ability of RA to induce growth arrest are markedly impaired in PML-/- cells and mice. PML is required for proper RARalpha transcriptional function acting as a transcriptional coactivator. Thus, X and RARalpha pathways can cross talk. It remains to be seen if the same is true for other X proteins

Figure 3 Distinct target genes for the X-RARalpha fusion proteins? The phenotype observed in the various X-RARalpha TM has highlighted the different biological role of these fusion proteins (block of differentiation and APL-like leukemia in PML-RARalpha TM; myeloproliferative CML-like disorder in PLZF-RARalpha TM). X-RARalpha may commonly deregulate a subset of RARalpha target genes which are critical for leukemogenesis (intersection of the two sets), while fusion protein specific gene clusters could dictate these biological differences. The transcriptional specificity could be conferred by the variable X moiety. Alternatively, the various fusion proteins might regulate an identical target gene set, but these genes could be differentially expressed in the presence of distinct X-RARalpha fusion proteins because of the variable X moiety

Figure 4 Common biological functions or shared molecular pathways by the X protein of APL? The various known and yet to be characterized translocation partners of RARalpha could control common molecular pathways in turn regulating cell growth, survival and differentiation

Figure 5 A unified model for the molecular pathogenesis of APL. In vivo analysis of TM and KO mice supports a model by which the concomitant activity of X-RARalpha and RARalpha-X fusion proteins is essential in APL pathogenesis. The deregulation of shared X pathways, in turn cross talking with the RARalpha-RXR pathway, may represent the key, albeit not sufficient, molecular event underlying APL pathogenesis

29 October 2001, Volume 20, Number 49, Pages 7216-7222
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