Disease |
Acute myeloid leukemia (AML) |
Phenotype / cell stem origin |
Acute promyelocytic leukemia (AML-M3 according to the FAB classification) |
Etiology | Exceptional; only 7 cases with balanced t(5;17)(q35;q12-21) translocation and the underlying NPM1/RARA fusion have been identified (5 males and 2 females, aged 2.5 to 52 years). There were 2 adult males, aged 29 and 52 years and 4 patients were pediatric cases, among them 2 were 12-year-old males and 2 were 2.5 and 9-year-old females (Table 1). |
Clinics | Disseminated intravascular coagulation was present at diagnosis in one case; remission obtained with chemotherapy and/or ATRA; first relapse at 7 and 5 months in 2 cases (Corey et al., 1994 ; Hummel et al., 1999). The 6-month-old boy described by Otsubo et al., presented with cutaneous mastocytosis and aleukemic leukemia cutis that regressed without any therapy within 6 months. Both adult patients also presented with myeloid sarcoma, therefore it is likely that it may occur frequently in NPM1/RARA associated APL (Nicci et., 2005; Kikuma et al.,2015). Table 1. Reported cases with t(5;17)(q35;q12-21) and confirmed NPM1-RARA fusion. | Sex/Age (years) | Karyotype | Clinics | 1. | F/2.5 | 46,XX,t(5;17)(q32;q12) 48,XX,t(5;17),+ 2mar | Therapy with ATRA while in partial remission, relapsed within 2 weeks of ATRA cessation. | 2. | M/12 | 47,XY,t(5;17)(q35;q21),der(8)(p23), der(10)(q26),del(12)(q13q22),del(1)(q12q14),-16,-18,+21,+22,+mar | Treated initially with chemotherapy, relapse occurred after 5 months. After therapy with ATRA remission was obtained, followed by bone marrow transplantation, but relapsed and remained refractory to further therapy. | 3. | F/9 | 46,XX,ins(3;5)(q26;q13q13),t(5;17)(q34;q21) | Therapy with ATRA as a part of induction therapy; alive in remission at 29 months. | 4. | M/12 | 46,XY,t(5;17)(q35;q21),del(12)(p13) | Died of cerebral hemorrhage after 5 days of ATRA treatment. | 5. | M/29 | 46,XY,t(5;17)(q35;q21) | Presented with granulocytic sarcoma; therapy with ATRA resulted in complete cytogenetic but not a molecular remission, relapsed at 22 months; treated with one course of arsenic trioxide. | 6. | M/4 | 46,XY,t(5;17)(q35;q12),i(21)(q10) | Presented with cutaneous mastocytosis and leukemia cutis at the age of 6 months with spontaneous regression within 6 month; followed by leukemia development at 4 years; remission to ATRA. | 7. | M/52 | 46,XY,t(5;17)(q35;q12) | Preceded by myeloid sarcoma; induction therapy including ATRA resulted in complete hematological and molecular remission. | Abbreviations: M, male; F, female; ATRA; all-trans-retinoic acid. 1. Corey et al., 1994 and Redner et al., 1996. 2. Hummel et al., 1999; 3. Grimwade et al., 2000; 4. Xu et al., 2001; 5. Nicci et al., 2005; 6. Otsubo et al., 2012; Kikuma et al., 2015. |
Cytology | Hypergranular and hypogranular bilobed promyelocytes; absence of Auer rods; typical microspeckeled pattern with anti-RARa antibodies; terminal differentiation of blasts and promyelocytes in vitro with ATRA. |
Prognosis | The 2.5 years-old child (Corey et al., 1994; Redner et al., 1996) was treated with ATRA while in partial remission and relapsed shortly after ATRA cessation. One of the 12-years old males (Hummel et al., 1999) received chemotherapy in induction and consolidation and relapsed after 5 months; remission was obtained with Ara-C and ATRA therapy followed by allogenic BM transplantation, but relapsed with therapy refractoriness. The second 12-years old male who presented with severe DIC died of cerebral hemorrhage after 5 days of ATRA treatment (Xu et al., 2001). The 9-year-old female was treated with ATRA as a part of induction therapy and was alive in first CR at 29 months (Grimwade et al 2000). The last pediatric patient presented with aleukemic leukemia cutis and t(5;17)(q35;q12) NPM1/RARA fusion at the age of 6-month-old (Kanegane et al., 2009; Otsubo et al., 2012). He showed no sign of leukemia without any therapy after 12 months, except for the presence of NPM1-RARA transcript in the bone marrow, but developed APL at the age of 4 years with complete remission to ATRA. Both adult patients received ATRA as part of induction therapy, resulting in cytogenetic but not a molecular remission in 1 patient who relapsed at 22 months after diagnosis (Nicci et al., 2005), and in complete hematological and molecular remission in the other case (Kikuma et al., 2015). From these data, the response to ATRA is difficult to assess since it was not part of induction treatment in some cases and due to the limited number of patients. However, patients with NPM1/RARA fusion appear to be sensitive to ATRA (Hummel et al., 1999; Grimwade et al., 2000; Kikuma et al., 2015) and cells bearing the t(5;17) terminally differentiate in its response (Redner et al., 1996), indicating that ATRA can be used to treat NPM1/RARA-positive APL patients. It is also possible that the presence of the additional/complex karyotypic abnormalities may be related to the prognosis in this group of patients. |
Variant and masked translocations in acute promyelocytic leukemia. |
Brunel V, Lafage-Pochitaloff M, Alcalay M, Pelicci PG, Birg F |
Leukemia & lymphoma. 1996 ; 22 (3-4) : 221-228. |
PMID 8819070 |
|
Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia. |
Buijs A, Bruin M. |
Leukemia 2007 May;21(5):1104-8. |
PMID 17301809 |
|
Acute promyelocytic leukemia with a STAT5b-RAR? fusion transcript defined by array-CGH, FISH, and RT-PCR. |
Chen H, Pan J, Yao L, Wu L, Zhu J, Wang W, Liu C, Han Q, Du G, Cen J, Xue Y, Wu D, Sun M, Chen S. |
Cancer Genet 2012 Jun;205(6):327-31. |
PMID 22749039 |
|
TBLR1 fuses to retinoid acid receptor ? in a variant t(3;17)(q26;q21) translocation of acute promyelocytic leukemia. |
Chen Y, Li S, Zhou C, Li C, Ru K, Rao Q, Xing H, Tian Z, Tang K, Mi Y, Wang B, Wang M, Wang J. |
Blood 2014 Aug 7;124(6):936-45. |
PMID 24782508 |
|
Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARalpha and NPM-RARalpha. |
Cheng GX, Zhu XH, Men XQ, Wang L, Huang QH, Jin XL, Xiong SM, Zhu J, Guo WM, Chen JQ, Xu SF, So E, Chan LC, Waxman S, Zelent A, Chen GQ, Dong S, Liu JX, Chen SJ |
Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (11) : 6318-6323. |
PMID 10339585 |
|
A non-classical translocation involving 17q12 (retinoic acid receptor alpha) in acute promyelocytic leukemia (APML) with atypical features. |
Corey SJ, Locker J, Oliveri DR, Shekhter-Levin S, Redner RL, Penchansky L, Gollin SM |
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1994 ; 8 (8) : 1350-1353. |
PMID 8057672 |
|
RARA fusion genes in acute promyelocytic leukemia: a review. |
De Braekeleer E, Douet-Guilbert N, De Braekeleer M. |
Expert Rev Hematol 2014 Jun;7(3):347-57. |
PMID 24720386 |
|
The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. |
Grimwade D |
British journal of haematology. 1999 ; 106 (3) : 591-613. |
PMID 10468848 |
|
Deregulation of NPM and PLZF in a variant t(5;17) case of acute promyelocytic leukemia. |
Hummel JL, Wells RA, Dubé ID, Licht JD, Kamel-Reid S |
Oncogene. 1999 ; 18 (3) : 633-641. |
PMID 9989813 |
|
Successful treatment of acute promyelocytic leukemia with a t(X;17)(p11.4;q21) and BCOR-RARA fusion gene. |
Ichikawa S, Ichikawa S, Ishikawa I, Takahashi T, Fujiwara T, Harigae H. |
Cancer Genet 2015 Apr;208(4):162-3. |
PMID 25790901 |
|
Spontaneous regression of aleukemic leukemia cutis harboring a NPM/RARA fusion gene in an infant with cutaneous mastocytosis. |
Kanegane H, Nomura K, Abe A, Makino T, Ishizawa S, Shimizu T, Naoe T, Miyawaki T. |
Int J Hematol 2009 Jan;89(1):86-90. |
PMID 19052694 |
|
A new transcriptional variant and small azurophilic granules in an acute promyelocytic leukemia case with NPM1/RARA fusion gene. |
Kikuma T, Nakamachi Y, Noguchi Y, Okazaki Y, Shimomura D, Yakushijin K, Yamamoto K, Matsuoka H, Minami H, Itoh T, Kawano S. |
Int J Hematol 2015 Dec;102(6):713-8. |
PMID 26342691 |
|
Acute promyelocytic leukemia following aleukemic leukemia cutis harboring NPM/RARA fusion gene. |
Otsubo K, Horie S, Nomura K, Miyawaki T, Abe A, Kanegane H. |
Pediatr Blood Cancer 2012 Nov;59(5):959-60. |
PMID 22573339 |
|
PML, PLZF and NPM genes in the molecular pathogenesis of acute promyelocytic leukemia. |
Pandolfi PP |
Haematologica. 1996 ; 81 (5) : 472-482. |
PMID 8952164 |
|
Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. |
Redner RL, Corey SJ, Rush EA |
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1997 ; 11 (7) : 1014-1016. |
PMID 9204984 |
|
The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. |
Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ |
Blood. 1996 ; 87 (3) : 882-886. |
PMID 8562957 |
|
OBFC2A/RARA: a novel fusion gene in variant acute promyelocytic leukemia. |
Won D, Shin SY, Park CJ, Jang S, Chi HS, Lee KH, Lee JO, Seo EJ. |
Blood 2013 Feb 21;121(8):1432-5. |
PMID 23287866 |
|
Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia. |
Yin CC, Jain N, Mehrotra M, Zhagn J, Protopopov A, Zuo Z, Pemmaraju N, DiNardo C, Hirsch-Ginsberg C, Wang SA, Medeiros LJ, Chin L, Patel KP, Ravandi F, Futreal A, Bueso-Ramos CE. |
J Natl Compr Canc Netw 2015 Jan;13(1):19-22. |
PMID 25583766 |
|