MLL starts at 118307.205 from pter, and CBL at 119076.986; they are normally separated by 29 known genes, which were apparently deleted in the case under study.

KMT2A (myeloid/lymphoid or mixed lineage leukemia)

11q23.3

A major transcript of 14982 bp produces a 3969 amino acids protein from 36 of the 37 exons. Contains from N-term to C-term a binding site for MEN1, 3 AT hooks (binds to the minor grove of DNA); 2 speckled nuclear localisation signals; 2 repression domains RD1 and RD2: RD1 or CXXC: cystein methyl transferase, binds CpG rich DNA, has a transcriptional repression activity; RD2 recruits histone desacetylases HDAC1 and HDAC2; 3 plant homeodomains (cystein rich zinc finger domains, with homodimerization properties), 1 bromodomain (may bind acetylated histones), and 1 plant homeodomain; these domains may be involved in protein-protein interaction; a FYRN and a FRYC domain; a transactivation domain which binds CBP; may acetylates H3 and H4 in the HOX area; a SET domain: methyltransferase; methylates H3, including histones in the HOX area for allowing chromatin to be open to transcription. MLL is cleaved by taspase 1 into 2 proteins before entering the nucleus: a p300/320 N-term protein called MLL-N, and a p180 C-term protein, called MLL-C. The FYRN and a FRYC domains of native MLL associate MLL-N and MLL-C in a stable complex; they form a multiprotein complex with transcription factor TFIID. General transcription factor; maintains HOX genes expression in undifferentiated cells. Major regulator of hematopoiesis and embryonic development; role in cell cycle regulation.

CBL (Cas-Br-M (murine) ecotropic retroviral transforming sequence)

11q23.3

Characterized by an N-terminal phosphotyrosine kinase-binding domain involved in protein-protein interaction, a short linker region, a zinc-binding RING-finger domain mediating the E3 ubiquitin ligase activity, proline-rich regions which mediate interactions with SH3-domain-containing proteins, and a C-terminal UBA (ubiquitin-associated) domain which enables homodimer formation, and also interacts with ubiquitin.

CBL is a member of the family of E3 ubiquitin ligases (CBL, CBLB and CBLC) that negatively regulates many signaling pathways downstream of membrane receptor tyrosine kinases, and also some non-receptor tyrosine-protein kinase (e.g. HCK). CBL is an adaptor protein. CBL forms the "CBL interactome" with associated proteins such as ubiquitin, SH3KBP1/CIN85, ARHGEF7/COOL1/PIXB, PDCD6IP/ALIX/AIP1, and TSG101. CBL is a regulator of cell growth, through the regulation of pathways such as PI3K/AKT/MTOR and RAS/RAF/MAPK. Acts as a tumor-suppressor gene (reviews in Thien and Langdon, 2005; Dikic and Schmidt, 2007).

Mutations located in the RING finger domain or the linker region were found in a syndrome with clinical features overlapping Noonan syndrome (Martinelli et al., 2010).

CBL mutations have been found in myeloproliferative/myelodysplastic syndromes, causing the loss of its E3-ubiquitin ligase activity, and an increase in cell proliferation (Aranaz et al., 2012).