Aml With Rearrangements Of Band 11q23 And The Mll Gene

This category represents approximately 4% of cases of adult AML, but rearrangements involving band 11q23 and the MLL gene (also known as ALL1, HRX, and HTRX) are three to four times more common in children with AML, being especially frequent among infants aged 12 months or less, 43-58% of whom carry an 11q23/MLL abnormality.13 At both the cytogenetic and molecular genetic level, AML with the 11q23/MLL rearrangements is extremely heterogeneous. Well over 30 different balanced chromosome abnormalities, mostly translocations but also inversions, insertions, and interstitial deletions, involving band 11q23 and another chromosome locus have been reported.536 The most common of these is t(9;11)(p22;q23), resulting in the AF9-MLL gene fusion; other more frequent recurrent translocations and fusion genes in AML include t(6;11)(q27;q23)/AF6-MLL, t(11;19)(q23;p13.1)/MLL-ELL, and t(11;19)(q23;p13.3)/MLL-MLLT1.

In some studies, patients with various 11q23/MLL rearrangements have been included in the same cyto-genetic category and classified as having either adverse9 or intermediate8 prognosis. However, increasing evidence suggests that prognosis of patients with 11q23/MLL rearrangements depends on the partner chromosome/gene involved, with t(9;11)-positive patients having a better prognosis,37,38 which places them in the intermediate cytogenetic risk group.10 The survival of adults with t(6;11) and t(11;19)(q23;p13.1) studied by Cancer and Leukemia Group B (CALGB) was significantly shorter than that of the cytogeneti-cally normal group, and consequently they were assigned to the adverse-risk group for survival.10

The MLL gene is a homeotic regulator that shares homology to sequences of the Drosophila trithorax gene. It encodes a nearly 430-kd protein. The C-termi-nus of MLL positively regulates HOX gene expression during development of hematopoietic stem cells. The N-terminus contains an AT hook region functioning as a DNA-binding domain and a region similar to the noncatalytic domain of methyltransferases.

Additionally, amplification of the MLL gene, without rearrangements of the gene, has been recently recognized as a recurrent aberration in patients with AML and myelodysplastic syndromes (MDS), a complex karyotype, and results in an adverse progno-sis.39-41 MLL amplification was shown to result in overexpression of the gene and MLL gain of function because it was associated with increased expression of one of its physiologic downstream targets, HOXA9.42

In addition to rearrangements generated by chromosome translocations, the MLL gene can also be

Table 2.3 Genetic anomalies that impact prognosis of AML patients with normal cytogenetics

Genetic rearrangement Prognostic significance

Internal tandem duplication CRD, DFS, and survival of the FLT3 gene significantly shorter for patients with FLT3 ITD compared with patients without FLT3 ITD; especially, poor outcome for FLT3 ITD patients with no expression of an FLT3 wild-type allele or a high FLT3 mutant/wildtype allele ratio

Loss-of-function mutations CRD and survival of the CEBPA gene significantly longer for patients with the CEBPA gene mutations compared with patients without mutated CEBPA

Partial tandem duplication CRD and EFS significantly of the MLL gene shorter for patients with MLL

PTD compared with patients without MLL PTD

Overexpression of the DFS, EFS, and survival

BAALC gene significantly shorter for patients with high expression of BAALC compared with low BAALC expression patients

Mutations of the NPMI CR rates, EFS, RFS, DFS, gene and OS significantly better for patients with NPMI mutations who do not harbor FLT3 ITD

CRD, CR duration; DFS, disease-free survival; EFS, event-free survival; RFS, relapse-free survival; OS, overall survival.

rearranged in AML patients without structural chromosome abnormalities involving band 11q23. These MLL rearrangements occur in the majority of patients with isolated trisomy 1143 and in 8-11% of karyotyp-ically normal adults with de novo AML,4445 and result from a PTD spanning exons 5 through 11 or, less frequently, exons 5 through 12.43-46 Among patients with normal cytogenetics, the MLL PTD confers poor prognosis (Table 2.3), and represents an independent adverse prognostic factor for remission duration.45

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