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Editorials
appears that such abnormalities are mostly observed dur- ing the first two years of TKI therapy. While there is a significant risk of a second myeloid malignancy in patients with -7 CCA/Ph-, less than half of these patients will develop MDS/AML. The aggregate data provide evi- dence in support of the commonly held view that pre- emptive therapeutic strategies are not justified in all patients with detectable -7 CCA/Ph-. Nevertheless, once a diagnosis of AML is confirmed in these patients, inten- sive treatment strategies, including allogeneic BM trans- plantation, are ineffective in most patients. One may speculate on the role of TKI in the mechanism of MDS development and the presence of -7/del(7q) CCA/Ph- abnormalities. The mutagenic effect of TKI on hematopoietic stem cells is not yet fully understood. However, it has been reported that a gastrointestinal stromal tumor patient developed MDS with monosomy 7 during imatinib treatment, suggesting that imatinib plays a direct role in causing MDS.12
The routine monitoring of CML patients is currently molecular assessment of the response. However, cytoge- netic analysis is still relevant and should be performed with a BM smear certainly in cases of cytopenia during TKI therapy. Signs of dysplasia with -7 CCA/Ph- cells should be considered as a red signal and a switch to alter- native treatment be discussed.
References
1. Guilhot F. Cytogenetics in CML: more important than you think. Blood. 2016;127(22):2661-2662.
2. WangW,CortesJE,TangG,etal.Riskstratificationofchromosomal abnormalities in chronic myelogenous leukemia in the era of tyro- sine kinase inhibitor therapy. Blood. 2016;127(22):2742-2750.
3. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-884.
4. National Comprehensive Cancer Network (NCCN). Chronic myeloid leukemia (version 1.2019). Available at: https://www.nccn.org.
5. Groves MJ, Sales M, Baker L, Griffiths M, Pratt N, Tauro S. Factors influencing a second myeloid malignancy in patients with Philadelphia-negative -7 or del(7q) clones during tyrosine kinase inhibitor therapy for chronic myeloid leukemia. Cancer Genet. 2011;204(1):39-44.
6. Wasilewska EM, Panasiuk B, Gniot M, et al. Clonal chromosomal aberrations in Philadelphia negative cells such as monosomy 7 and trisomy 8 may persist for years with no impact on the long-term out- come in patients with chronic myeloid leukemia. Cancer Genet. 2017;216-217:1-9.
7. Issa GC, Kantarjian HM, Gonzalez GN, et al. Clonal chromosomal abnormalities appearing in Philadelphia chromosome-negative metaphases during CML treatment. Blood. 2017;130(19):2084-2091.
8. Bidet A, Dulucq S, Smol T, et al. Poor prognosis of chromosome 7 clonal aberrations in Philadelphia-negative metaphases and rele- vance of potential underlying myelodysplastic features in chronic myeloid leukaemia. Hematologica. 2019;104(6):1150-1155.
9. Gambacorti-Passeri C, Giudici G, le Coutre P, et al. Non-random chromosomal abnormalities in Ph-negative bone marrow (BM) cells from CML patients achieving major cytogenetic responses (MCR) with STI571 (GleevecTM). Blood. 2001;98:257b (Abstr. 4762).
10. AndersenMK,Pedersen-BjergaardJ,KjeldsenL,DufvaIH,Brøndum- Nielsen K. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia. 2002;16(7):1390-1393.
11. Karimata K, Masuko M, Ushiki T, et al. Myelodysplastic Syndrome with Ph Negative Monosomy 7 Chromosome following Transient Bone Marrow Dysplasia during Imatinib Treatment for Chronic Myeloid Leukemia. Intern Med. 2011;50(5):481-485.
12. PitiniV,ArrigoC,SautaMG,AltavillaG.Myelodysplasticsyndrome appearing during imatinib mesylate therapy in a patient with GIST. Leuk Res. 2009;33(9):143-144.
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Another piece of the puzzle added to understand t(4;11) leukemia better
Rolf Marschalek
Institute of Pharmaceutical Biology / Diagnostic Center of Acute Leukemia, University of Frankfurt, Frankfurt/Main, Germany; E-mail: ROLF MARSCHALEK - Rolf.Marschalek@em.uni-frankfurt.de
doi:10.3324/haematol.2018.213397
The story about t(4;11) leukemia, involving the MLL/KMT2A gene from chromosome 11q23.3 and the AF4/AFF1 gene from chromosome 4q21, is still a mystery. The study by Agraz-Doblas et al., published in this issue of Haematologica, adds some new and important information regarding the mysterious pathomechanism.1 Agraz-Doblas et al. showed, for the first time, that the therapeutic outlook of patients with expression of both reciprocal MLL fusions, MLL-AF4 and AF4-MLL, is prom- ising, but only 50% of the investigated patients seem to have this favorable condition; patients expressing only the MLL-AF4 allele have an event-free survival of 10% and an overall survival of 30%. Moreover, only leukemic cells expressing both fusion alleles display the typical HOXA signature.
The fact that t(4;11) patients can be divided into two subgroups on the basis of HOXA transcription was first
recognized by Trentin et al. in 2009,2 and later confirmed by Stam et al. and Kang et al. in 2010 and 2012, respective-
3,4
ly. The missing HOXA transcription was correlated with
overexpression of either IRX1 or IRX22,4 and a 3-fold high- er relapse rate.3,4 Experimental overexpression of IRX1 revealed an interesting mechanism because it resulted in EGR1-3 expression.5 EGR1 and EGR2 both control the p21CIP1 gene and, thus, shut down the cell cycle and may even induce cellular quiescence, a known mechanism of resistance to treatment. CDK6 counteracts the actions of EGR proteins.6 The second mechanism involves the IRX proteins, which are able to turn on HOXB4, a known stem cell marker of hematopoietic cells that activates fac- tors such as TAL1, GATA factors, TGFB1, etc. Thus, expression of MLL-AF4 alone - with upregulated IRX pro- teins but without HOXA expression - may provoke treat- ment resistance or a stem cell-like mechanism which is
haematologica | 2019; 104(6)